Heterocyclic inhibitors of mct4

ABSTRACT

Disclosed herein are compounds and compositions useful in the treatment of MCT4 mediated diseases, such as proliferative and inflammatory diseases, having the structure of Formula I: 
     
       
         
         
             
             
         
       
     
     Methods of inhibition MCT4 activity in a human or animal subject are also provided.

This application is a continuation of U.S. patent application Ser. No.15/839,539, filed Dec. 12, 2017, and entitled “Heterocyclic Inhibitorsof MCT4,” which claims the benefit of priority of U.S. ProvisionalApplication No. 62/433,113, filed Dec. 12, 2016, the contents of whichare incorporated by reference as if written herein in their entiretiesfor all purposes.

Disclosed herein are new heterocyclic compounds and compositions andtheir application as pharmaceuticals for the treatment of disease.Methods of inhibition of MCT4 activity in a human or animal subject arealso provided for the treatment diseases such as cancer.

Lactic acid export from glycolytic cells is typically mediated by themonocarboxylate transporter MCT4. MCT4 exhibits weak affinity forlactate (K_(m)=28 mM) coupled with a high turnover rate, allowing rapidexport of large amounts of lactic acid. MCT4 expression is normallylimited to highly glycolytic tissues such as white muscle fibers,lymphocytes, astrocytes, and Sertoli cells. Though MCT4 is absent frommost normal tissues, MCT4 expression is highly upregulated, andcorrelates with poor survival, in many cancer indications, includingcolorectal cancer, glioma, head and neck cancer, triple-negative breastcancer, prostate cancer, KRAS mutant lung cancer, liver cancer, andkidney cancer.

The correlation of MCT4 expression and poor cancer outcome appears to beof significant functional consequence in multiple cancer models. Stableexpression of MCT4 is highly tumorigenic in a respiration-impaired,Ras-transformed fibroblast xenograft model. Conversely, MCT4 silencingslows or ablates tumor growth in xenograft models of breast cancer,colorectal cancer, and glioma. MCT4 expression is required forinflammatory cytokine IL-8-mediated angiogenesis in breast and coloncancer xenograft models. MCT4 has also been shown to play importantroles in cancer cell migration, invasion, and various aspects of theWarburg effect (e.g., proliferation on glucose, extracellularacidification, and lactate secretion).

Inhibition of MCT4-mediated lactic acid export may be an effectivestrategy to impair the Warburg effect in cancer. Unfortunately, nopotent and selective MCT4 inhibitors have been described. Moderate toweak MCT4 inhibitors are known (e.g., phloretin and□-CN-4-OH-cinnamate); however, these compounds promiscuously inhibit anumber of other transporters, including MCT1.

Thus, there is a need for potent and selective MCT4 inhibitors for usein the treatment or prevention of cancer.

DETAILED DESCRIPTION

Novel compounds and pharmaceutical compositions, certain of which havebeen found to inhibit MCT4 have been discovered, together with methodsof synthesizing and using the compounds including methods for thetreatment of MCT4-mediated diseases in a patient by administering thecompounds.

Provided is a compound of structural Formula I

or a salt thereof, wherein:

A¹, A², and A³ are independently chosen from N and C, wherein at leastone of A¹, A², and A³ is N;

L is chosen from a bond, methylene, and ethylene;

W is chosen from

X is H or null, or is chosen from alkenylamino, alkyl, aminoalkenyl, andaminoalkyl, any of which is optionally substituted with one to three R¹groups;

Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl,aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl, andheteroaryl, any of which is optionally substituted with one to three R²groups, or

X and Y together with the atoms to which they are attached may form anaryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, any of which isoptionally substituted with one to three R⁷ groups; and

Z is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl, any of which is optionally substituted with one to three R³groups;

each R¹ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy,cycloalkyl, aryl, heteroaryl;

each R² is independently chosen from alkyl, alkenyl, alkoxy,alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy,cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl,carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, or

two R², together with the intervening atoms, form a 5-7 memberedcycloalkyl or heterocycloalkyl ring;

each R³ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido,halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, and is optionally substituted with one to three R⁸ groups,or

two R³, together with the intervening atoms, form a 5-7 memberedcycloalkyl or heterocycloalkyl ring;

R⁴ and R⁵ are independently chosen from H and C₁-C₆alkyl, wherein R⁴ andR⁵ together comprise no more than 6 carbons, or

R⁴ and R⁵, together with the atoms to which they are attached, form a3-7 membered cycloalkyl or heterocycloalkyl ring;

R⁶ is chosen from H and C₁-C₄alkyl;

each R⁷ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy,cycloalkyl, aryl, and heteroaryl; and

each R⁸ is independently chosen from cyano, halo, hydroxy, and oxo.

Certain compounds disclosed herein may possess useful MCT4 inhibitingactivity, and may be used in the treatment or prophylaxis of a diseaseor condition in which MCT4 plays an active role. Thus, in broad aspect,certain embodiments also provide pharmaceutical compositions comprisingone or more compounds disclosed herein together with a pharmaceuticallyacceptable carrier, as well as methods of making and using the compoundsand compositions. Certain embodiments provide methods for inhibitingMCT4. Other embodiments provide methods for treating a MCT4-mediateddisorder in a patient in need of such treatment, comprisingadministering to said patient a therapeutically effective amount of acompound or composition according to the present invention. Alsoprovided is the use of certain compounds disclosed herein for use in themanufacture of a medicament for the treatment of a disease or conditionameliorated by the inhibition of MCT4.

In certain embodiments, X is chosen from alkenylamino, alkyl,aminoalkenyl, aminoalkyl, and H; and Y is chosen from alkenyl,alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl, andheteroaryl.

In certain embodiments, X and Y together with the atoms to which theyare attached may form an aryl, cycloalkyl, heteroaryl, orheterocycloalkyl ring.

In certain embodiments, exactly two of A¹, A², and A³ is N.

In certain embodiments, exactly one of A¹, A², and A³ is N.

In certain embodiments, A¹ and A² are C; and A³ is N.

In certain embodiments, X is hydrogen.

In certain embodiments, W is chosen from

In certain embodiments, W is chosen from

In certain embodiments, W is

In certain embodiments, Y is chosen from aryl and heteroaryl, any ofwhich is optionally substituted with one to three R² groups.

In certain embodiments, Y is chosen from phenyl, thienyl, thiazolyl,quinolinyl, isoquinolinyl, cinnolinyl, indazolyl, and indolyl.

In certain embodiments, Y is chosen from quinolinyl, isoquinolinyl,cinnolinyl, indazolyl, and indolyl.

In certain embodiments, Y is chosen from phenyl, thienyl, and thiazolyl.

In certain embodiments, Z is chosen from phenyl, pyridinyl, quinolinyl,isoquinolinyl, cinnolinyl, indazolyl, and indolyl.

In certain embodiments, Z is chosen from phenyl and pyridinyl.

In certain embodiments, each R² is independently chosen from alkenyl,alkoxy, alkoxyalkyl, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl,aryl, halo, heteroaryl, and haloalkyl.

In certain embodiments, each R² is independently chosen from alkoxy,alkoxyalkyl, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo,and haloalkyl.

In certain embodiments, two R², together with the intervening atoms,form a 5-7 membered cycloalkyl or heterocycloalkyl ring.

In certain embodiments, each R³ is independently chosen from alkenyl,alkoxy, alkyl, aryl, halo, heteroaryl, and haloalkyl.

In certain embodiments, each R³ is independently chosen from alkoxy,alkyl, aryl, and heteroaryl.

In certain embodiments, two R³, together with the intervening atoms,form a 5-7 membered cycloalkyl or heterocycloalkyl ring.

In certain embodiments, each R³ is alkoxy.

In certain embodiments, each R³ is methoxy.

In certain embodiments, each R³ is halo.

In certain embodiments, each R³ is independently selected from F, Br,and I.

In certain embodiments, each R³ is F.

In certain embodiments, R⁴ and R⁵ are independently chosen from H andC₁-C₂alkyl.

In certain embodiments, R⁴ and R⁵ are independently chosen from H andmethyl.

In certain embodiments, R⁴ and R⁵, together with the atoms to which theyare attached, form a 3-7 membered cycloalkyl or heterocycloalkyl ring.

In certain embodiments, R⁶ is chosen from H and C₁-C₂alkyl.

In certain embodiments, R⁶ is chosen from H and methyl.

In certain embodiments, each R⁷ is independently chosen from alkyl,alkoxy, haloalkyl, haloalkoxy, amino, carboxamido, halo, cyano, hydroxy,cycloalkyl, aryl, and heteroaryl.

In certain embodiments, each R⁷ is independently chosen from alkyl andalkoxy.

In certain embodiments, the compounds have structural formula Ia:

or a salt or tautomer thereof, wherein:

A⁵ is chosen from C—X and N;

A⁶ is chosen from C—Y and N;

and A⁷ are and A⁸ are chosen from the following combinations:

A⁷ is C and A⁸ is NH, or

A⁷ is N and A⁸ is N;

wherein at least one of A⁵, A⁶, and A⁷ is N;

L is chosen from a bond and methylene;

W is chosen from

X is H, or is chosen from alkenylamino, alkyl, aminoalkenyl, andaminoalkyl, any of which is optionally substituted with one to three R¹groups;

Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl,aryl, cycloalkyl, and heteroaryl, any of which is optionally substitutedwith one to three R² groups, or

X and Y together with the atoms to which they are attached may form anaryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring, any of which isoptionally substituted with one to three R⁷ groups; and

Z is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl, any of which is optionally substituted with one to three R³groups;

each R¹ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy,cycloalkyl, aryl, heteroaryl;

each R² is independently chosen from alkyl, alkenyl, alkoxy,alkoxyalkyl, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy,amino, carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl,and heteroaryl;

each R³ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy,cycloalkyl, aryl, and heteroaryl;

R⁴ and R⁵ are independently chosen from H and C₁-C₆alkyl, wherein R⁴ andR⁵ together comprise no more than 6 carbons;

R⁶ is chosen from H and C₁-C₄alkyl; and

each R⁷ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy,cycloalkyl, aryl, and heteroaryl.

In certain embodiments, the compounds have structural Formula II:

or a salt thereof, wherein:

L is chosen from a bond and methylene;

W is chosen from

Y is chosen from aryl, arylmethyl, arylamino, aryloxy, cycloalkyl,heterocycloalkyl, and heteroaryl, any of which is optionally substitutedwith one to three R² groups;

Z is chosen from aryl and heteroaryl, either of which is optionallysubstituted with one to three R³ groups;

each R² is independently chosen from alkyl, alkoxy, alkoxyalkyl,alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy,heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido,halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, or

two R², together with the intervening atoms, form a 5-7 memberedcycloalkyl or heterocycloalkyl ring;

each R³ is independently chosen from alkyl, alkoxy, haloalkyl,haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido,halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, and is optionally substituted with one to three R⁸ groups,or

two R³, together with the intervening atoms, form a 5-7 memberedcycloalkyl or heterocycloalkyl ring;

R⁴ and R⁵ are independently chosen from H and C₁-C₆alkyl, wherein R⁴ andR⁵ together comprise no more than 6 carbons and wherein at least one ofR⁴ and R⁵ is C₁-C₆alkyl, or

R⁴ and R⁵, together with the atoms to which they are attached, form a3-7 membered cycloalkyl or heterocycloalkyl ring;

R⁶ is chosen from H and C₁-C₄alkyl; and

each R⁸ is independently chosen from cyano, halo, hydroxy, and oxo.

In certain embodiments of structural formula II,

L is a bond; and

each R² is chosen from alkenyl, C₂-C₆alkoxy, cycloalkoxy,cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl, andhaloalkyl.

In certain embodiments of structural formula II,

Z is chosen from aryl and heteroaryl, either of which is substitutedwith one to three R³ groups;

each R² is chosen from alkenyl, C₂-C₆alkoxy, cycloalkoxy,cycloalkylmethoxy, haloalkoxy, alkyl, aryl, heteroaryl, and haloalkyl;and

each R³ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, amino, carboxamido, sulfonamido, cycloalkyl, aryl, andheteroaryl.

In certain embodiments of structural formula II,

Y is heteroaryl, and is substituted with one to three R² groups; and

each R² is chosen from alkenyl, C₂-C₆alkoxy, cycloalkoxy,cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl, andhaloalkyl.

In certain embodiments of structural formula II,

Y is selected from the group consisting of furyl, thienyl, pyrrolyl,imidazolyl, and oxazolyl, any of which is substituted with one to threeR² groups; and

each R² is chosen from alkenyl, C₂-C₆alkoxy, cycloalkoxy,cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl, andhaloalkyl.

In certain embodiments of structural formula II, at least one of R⁴ andR⁵ is H.

In certain embodiments of structural formula II, exactly one of R⁴ andR⁵ is H.

In certain embodiments, the compounds have structural Formula III:

or a salt thereof, wherein:

L is chosen from a bond and methylene;

Z is chosen from aryl and heteroaryl, either of which is optionallysubstituted with one or two R³ groups;

R^(2a) and R^(2b) are independently chosen from H, alkyl, alkoxy,haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, halo, cycloalkyl,and heterocycloalkyl;

each R³ is independently chosen from alkyl, alkoxy, haloalkyl,haloalkoxy, amino, aminoalkyl, carboxamido, halo, cyano, hydroxy, andcycloalkyl, and is optionally substituted with one or two R⁸ groups;

R⁴ and R⁵ are independently chosen from H and C₁-C₆alkyl, wherein R⁴ andR⁵ together comprise no more than 6 carbons and wherein at least one ofR⁴ and R⁵ is C₁-C₆alkyl, or

R⁴ and R⁵, together with the atoms to which they are attached, form a3-7 membered cycloalkyl or heterocycloalkyl ring;

R⁶ is chosen from H and methyl; and

each R⁸ is independently chosen from cyano, halo, hydroxy, and oxo.

In certain embodiments of structural formula III,

Z is chosen from quinolinyl, isoquinolinyl, cinnolinyl, indazolyl, andindolyl, any of which is optionally substituted with one to three R³groups; and

each R³ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy,cycloalkyl, aryl, and heteroaryl.

In certain embodiments of structural formula III, Z is chosen fromalkyl, cycloalkyl, and heterocycloalkyl, any of which is optionallysubstituted with one to three R³ groups;

In certain embodiments of structural formula III, R² is chosen fromalkenyl, C₂-C₆alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl,aryl, halo, heteroaryl, and haloalkyl.

In certain embodiments of structural formula III, R² is selected fromalkoxy, alkyl, halo, haloalkyl, and haloalkoxy.

In certain embodiments of structural formula III, each R³ isindependently chosen from alkenyl, alkoxy, alkyl, amino, aryl, halo,heteroaryl, and haloalkyl; and

In certain embodiments of structural formula III, Z is chosen fromalkyl, cycloalkyl, and heterocycloalkyl, any of which is optionallysubstituted with one to three R³ groups;

In certain embodiments of structural formula III,

L is a bond;

Z is chosen from aryl and heteroaryl, either of which is substitutedwith one to three R³ groups; and

each R³ is independently chosen from alkenyl, alkoxy, alkyl, amino,fluoro, bromo, and iodo.

In certain embodiments of structural formula III,

L is methylene;

Z is chosen from aryl and heteroaryl, either of which is substitutedwith one to three R³ groups; and

each R³ is independently chosen from alkenyl, C₂-C₆alkoxy, C₄-C₈alkyl,aryl, and iodo.

In certain embodiments of structural formula III,

L is a bond; and

Z is chosen from pyridin-3-yl and pyridin-4-yl, and is optionallysubstituted with one to three R³ groups.

In certain embodiments of structural formula III,

L is methylene; and

Z is pyridyl, and is optionally substituted with one to three R³ groups.

In certain embodiments of structural formula III,

L is methylene; and

Z is pyridyl, and is optionally substituted with two or three R³ groups.

In certain embodiments, the compounds have structural Formula IV:

or a salt thereof, wherein:

L is chosen from a bond and methylene;

W is chosen from

Z is chosen from alkyl, cycloalkyl, heterocycloalkyl, aryl andheteroaryl, any of which is optionally substituted with one to three R³groups;

each R³ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, amino, carboxamido, sulfonamido, halo, cyano, hydroxy,cycloalkyl, aryl, and heteroaryl;

R⁴ and R⁵ are independently chosen from H and C₁-C₆alkyl, wherein R⁴ andR⁵ together comprise no more than 6 carbons;

R⁶ is chosen from H and C₁-C₄alkyl; and

n is selected from 1, 2, and 3.

In certain embodiments, the compounds have structural Formula V:

or a salt thereof, wherein:

L is chosen from a bond and methylene;

Y is chosen from phenyl, thienyl, furyl, thiazolyl, and oxazolyl, any ofwhich is optionally substituted with one or two R² groups, or

each R² is independently chosen from alkoxy, alkylthio, haloalkoxy,cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, and halo;

R^(3a) is chosen from H, alkoxy, haloalkoxy, cycloalkoxy, amino, andhalo;

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl, or

R⁴ and R⁵, together with the atoms to which they are attached, form a3-7 membered cycloalkyl or heterocycloalkyl ring; and

R⁶ is chosen from H and C₁-C₄alkyl.

In certain embodiments, the compounds have structural Formula VI:

or a salt thereof, wherein:

L is chosen from a bond and methylene;

R^(2a) is chosen from alkoxy, alkylthio, haloalkoxy, cycloalkoxy,cycloalkylmethoxy, heterocycloalkylmethoxy, and halo;

R^(3a) is chosen from H, alkoxy, haloalkoxy, cycloalkoxy, amino, andhalo;

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl, or

R⁴ and R⁵, together with the atoms to which they are attached, form a3-7 membered cycloalkyl or heterocycloalkyl ring; and

R⁶ is chosen from H and C₁-C₄alkyl.

In certain embodiments, the compounds have structural Formula VII:

or a salt thereof, wherein:

Y is chosen from aryl, arylmethyl, arylamino, aryloxy, cycloalkyl,heterocycloalkyl, and heteroaryl, any of which is optionally substitutedwith one to three R² groups, or

Z is chosen from aryl and heteroaryl, either of which is optionallysubstituted with one to three R³ groups;

each R² is independently chosen from alkyl, alkenyl, alkoxy,alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy,cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl,carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, or

two R², together with the intervening atoms, form a 5-7 memberedcycloalkyl or heterocycloalkyl ring;

each R³ is independently chosen from alkyl, alkenyl, alkoxy, haloalkyl,haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido,halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, and is optionally substituted with one to three R⁸ groups,or

two R³, together with the intervening atoms, form a 5-7 memberedcycloalkyl or heterocycloalkyl ring;

R⁴ and R⁵ are independently chosen from C₁-C₆alkyl, wherein exactly oneof R⁴ and R⁵ is methyl;

R⁶ is chosen from H and C₁-C₄alkyl; and

each R⁸ is independently chosen from cyano, halo, hydroxy, and oxo.

In certain embodiments, the compounds have structural Formula VII:

or a salt thereof, wherein:

L is chosen from a bond and methylene;

W is chosen from

Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl,aryl, arylmethyl, arylamino, aryloxy, cycloalkyl, heterocycloalkyl, andheteroaryl, any of which is optionally substituted with one to three R²groups;

each R² is independently chosen from alkyl, alkenyl, alkoxy,alkoxyalkyl, alkylthio, haloalkyl, haloalkoxy, cycloalkoxy,cycloalkylmethoxy, heterocycloalkylmethoxy, amino, aminoalkyl,carboxamido, sulfonamido, halo, cyano, hydroxy, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl;

n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl);

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl; and

R⁶ is chosen from H and C₁-C₄alkyl.

In certain embodiments of structural formula VII, Y is chosen from aryland heteroaryl, either of which is optionally substituted with one tothree R² groups.

In certain embodiments of structural formula VII, each R² isindependently chosen from alkoxy, cycloalkoxy, haloalkoxy, alkyl, halo,and haloalkyl.

In certain embodiments of structural formula VII W is

In certain embodiments of structural formula VII, n is 1, formingazetidin-1-yl.

In certain embodiments of structural formula VII, L is a bond.

In certain embodiments, the compounds have structural Formula VIII:

or a salt thereof, wherein:

L is chosen from a bond and methylene;

Y is chosen from phenyl, indazolyl, thienyl, indazolyl, and indolyl, anyof which is optionally substituted with one or two R² groups;

n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl);

each R² is independently chosen from alkyl, alkoxy, alkylthio,haloalkoxy, cycloalkoxy, cycloalkylmethoxy, heterocycloalkylmethoxy, andhalo;

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl; and

R⁶ is chosen from H and C₁-C₄alkyl.

In certain embodiments of structural formula VIII, Y is chosen fromphenyl and indazolyl, either of which is optionally substituted with oneor two R² groups.

In certain embodiments of structural formula VIII, each R² isindependently chosen from alkoxy, cycloalkoxy, haloalkoxy, alkyl, halo,and haloalkyl.

In certain embodiments of structural formula VIII, n is 1, formingazetidin-1-yl.

In certain embodiments of structural formula VIII, L is a bond.

In certain embodiments of structural formula VIII, Y is phenylsubstituted with one or two R² groups independently chosen from alkoxy,cycloalkoxy, haloalkoxy, alkyl, halo, and haloalkyl.

In certain embodiments of structural formula VIII, each R² isindependently chosen from C₁-C₄alkoxy, cyclopropoxy, cyclobutoxy, andC₁-C₃alkyl.

In certain embodiments of structural formula VIII, Y is indazolylsubstituted with an R² groups chosen from methyl, ethyl, and propyl.

In certain embodiments of structural formula VIII, Y is chosen from:

R^(2c) is chosen from C₁-C₄alkoxy and C₁-C₄cycloalkoxy;

R^(2d) is chosen from null and C₁-C₄alkoxy; and

R^(2e) is C₁-C₄alkyl.

In certain embodiments, the compounds have structural Formula IX:

or a salt thereof, wherein:

L is chosen from a bond and methylene;

W is chosen from

Y is chosen from aryl, arylmethyl, arylamino, aryloxy, cycloalkyl,heterocycloalkyl, and heteroaryl, any of which is optionally substitutedwith one to three R² groups;

Z is chosen from aryl and heteroaryl, either of which is optionallysubstituted with one to three R³ groups;

each R² is independently chosen from alkyl, alkoxy, alkoxyalkyl,alkylthio, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy,heterocycloalkylmethoxy, amino, aminoalkyl, carboxamido, sulfonamido,halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl;

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl; and

R⁶ is chosen from H and C₁-C₄alkyl.

In certain embodiments of structural formula IX, Y is chosen from aryland heteroaryl, either of which is optionally substituted with one tothree R² groups.

In certain embodiments of structural formula IX, each R² isindependently chosen from alkoxy, cycloalkoxy, haloalkoxy, alkyl, halo,and haloalkyl.

In certain embodiments of structural formula IX, W is

In certain embodiments of structural formula IX, L is a bond.

In certain embodiments of structural formula IX, Y is phenyl substitutedwith one or two R² groups independently chosen from alkoxy, cycloalkoxy,haloalkoxy, alkyl, halo, and haloalkyl.

In certain embodiments of structural formula IX, each R² isindependently chosen from C₁-C₄alkoxy, cyclopropoxy, cyclobutoxy, andC₁-C₃alkyl.

In certain embodiments, the compounds have structural Formula X:

or a salt thereof, wherein:

W is chosen from

R^(2e) is C₁-C₄alkyl;

L is chosen from a bond and methylene;

Z is chosen from aryl and heteroaryl, either of which is optionallysubstituted with one to three R³ groups;

each R³ is independently chosen from alkyl, alkoxy, haloalkyl,haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido,halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, and is optionally substituted with one to three R⁸ groups,or

two R³, together with the intervening atoms, form a 5-7 memberedcycloalkyl or heterocycloalkyl ring;

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl;

R⁶ is chosen from H and C₁-C₄alkyl; and

each R⁸ is independently chosen from cyano, halo, hydroxy, and oxo.

In certain embodiments of structural formula X, W is

In certain embodiments of structural formula X, L is a bond.

In certain embodiments of structural formula X, Z is chosen from phenyland indazolyl, either of which is optionally substituted with one tothree R³ groups.

In certain embodiments of structural formula X, Z is chosen from:

n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl);

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl;

R⁶ is chosen from H and C₁-C₄alkyl; and

R⁹ is chosen from halo, amino, and C₁-C₄alkoxy.

In certain embodiments of structural formula X, R⁹ is chosen fromchloro, dimethylamino, and ethoxy.

In certain embodiments of structural formula X, R⁹ is chosen from chloroand ethoxy.

In certain embodiments of structural formula X, n is 1, formingazetidin-1-yl.

In certain embodiments, the compounds have structural Formula XI:

or a salt thereof, wherein:

W is chosen from

n is 1, 2, or 3 (forming a cyclopropyl, cyclobutyl, or cyclopentyl);

L is chosen from a bond and methylene;

Z is chosen from aryl and heteroaryl, either of which is optionallysubstituted with one to three R³ groups;

each R³ is independently chosen from alkyl, alkoxy, haloalkyl,haloalkoxy, cycloalkoxy, amino, aminoalkyl, carboxamido, sulfonamido,halo, cyano, hydroxy, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, and is optionally substituted with one to three R⁸ groups,or

two R³, together with the intervening atoms, form a 5-7 memberedcycloalkyl or heterocycloalkyl ring;

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl;

R⁶ is chosen from H and C₁-C₄alkyl; and

each R⁸ is independently chosen from cyano, halo, hydroxy, and oxo.

In certain embodiments of structural formula XI, W is

In certain embodiments of structural formula XI, L is a bond.

In certain embodiments of structural formula XI, Z is chosen from phenyland indazolyl, either of which is optionally substituted with one tothree R³ groups.

In certain embodiments of structural formula XI, Z is chosen from:

n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl);

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl;

R⁶ is chosen from H and C₁-C₄alkyl; and

R⁹ is chosen from halo, amino, and C₁-C₄alkoxy.

In certain embodiments of structural formula XI, R⁹ is chosen fromchloro, dimethylamino, and ethoxy.

In certain embodiments of structural formula XI, R⁹ is chosen fromchloro and ethoxy.

In certain embodiments of structural formula XI, n is 1, formingazetidin-1-yl.

In certain embodiments, the compounds have structural Formula II:

or a salt thereof, wherein:

L is chosen from a bond and methylene;

W is chosen from

Y is chosen from:

R^(2e) is C₁-C₄alkyl;

Z is chosen from:

n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl);

R⁴ and R⁵ are independently chosen from C₁-C₃alkyl;

R⁶ is chosen from H and C₁-C₄alkyl; and

R⁹ is chosen from halo and C₁-C₄alkoxy.

In certain embodiments of structural formula II, W is

In certain embodiments of structural formula II, R⁹ is chosen fromchloro and ethoxy.

In certain embodiments of structural formula II, L is a bond.

In certain embodiments of structural formula II:

Y is

R^(2c) is chosen from C₁-C₄alkoxy and C₁-C₄cycloalkoxy; and

R^(2d) is chosen from null and C₁-C₄alkoxy.

In certain embodiments of structural formula II:

R^(2c) is chosen from methoxy, methylpropoxy, cyclopropoxy, andcyclobutoxy; and

R^(2d) is chosen from null and methoxy.

In certain embodiments of structural formula II:

Y is

and

R^(2e) is C₁-C₄alkyl.

In certain embodiments of structural formula II, R^(e)e is chosen fromethyl and propyl.

In certain embodiments of structural formula II, Z is

In certain embodiments of structural formula II, n is 1, formingazetidin-1-yl.

In certain embodiments of structural formula II, Z is

In certain embodiments of structural formula II, Z is

In certain embodiments of structural formula II, R⁹ is chosen fromchloro and ethoxy.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

As used herein, two embodiments are “mutually exclusive” when one isdefined to be something which is different than the other. For example,an embodiment wherein two groups combine to form a cycloalkyl ismutually exclusive with an embodiment in which one group is ethyl theother group is hydrogen. Similarly, an embodiment wherein one group isCH2 is mutually exclusive with an embodiment wherein the same group isNH.

Also provided is a compound chosen from the Examples disclosed herein.

The present invention also relates to a method of inhibiting at leastone MCT4 function comprising the step of contacting MCT4 with a compoundas described herein. The cell phenotype, cell proliferation, activity ofMCT4, change in biochemical output produced by active MCT4, expressionof MCT4, or binding of MCT4 with a natural binding partner may bemonitored. Such methods may be modes of treatment of disease, biologicalassays, cellular assays, biochemical assays, or the like.

Also provided herein is a method of treatment of a MCT4-mediated diseasecomprising the administration of a therapeutically effective amount of acompound as disclosed herein, or a salt thereof, to a patient in needthereof.

In certain embodiments, the disease is chosen from proliferativeinflammatory diseases.

In certain embodiments, the disease is a metabolic disease.

In certain embodiments, said metabolic disease is chosen from metabolicsyndrome, diabetes, dyslipidemia, fatty liver disease, non-alcoholicsteatohepatitis, obesity, and insulin resistance.

In certain embodiments, said diabetes is Type II diabetes.

In certain embodiments, said dyslipidemia is hyperlipidemia.

Further provided is a method for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as disclosed above to a patient, wherein the effect is selectedfrom the group consisting of reduction of triglycerides, reduction ofcholesterol, and reduction of hemoglobin A1c.

Further provided is the method as disclosed above wherein saidcholesterol is chosen from LDL and VLDL cholesterol.

Further provided is the method as disclosed above wherein saidtriglycerides are chosen from plasma triglycerides and livertriglycerides.

Also provided herein is a compound as disclosed herein for use as amedicament.

Also provided herein is a compound as disclosed herein for use as amedicament for the treatment of a MCT4-mediated disease.

Also provided is the use of a compound as disclosed herein as amedicament.

Also provided is the use of a compound as disclosed herein as amedicament for the treatment of a MCT4-mediated disease.

Also provided is a compound as disclosed herein for use in themanufacture of a medicament for the treatment of a MCT4-mediateddisease.

Also provided is the use of a compound as disclosed herein for thetreatment of a MCT4-mediated disease.

Also provided herein is a method of inhibition of MCT4 comprisingcontacting MCT4 with a compound as disclosed herein, or a salt thereof.

Also provided herein is a method for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as disclosed herein, or a salt thereof, to a patient, whereinthe effect is chosen from cognition enhancement.

In certain embodiments, the MCT4-mediated disease is chosen fromproliferative inflammatory diseases.

Also provided is a method of modulation of a MCT4-mediated function in asubject comprising the administration of a therapeutically effectiveamount of a compound as disclosed herein.

Also provided is a pharmaceutical composition comprising a compound asdisclosed herein, together with a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition is formulated fororal administration.

In certain embodiments, the oral pharmaceutical composition is chosenfrom a tablet and a capsule.

Abbreviations and Definitions

To facilitate understanding of the disclosure, a number of terms andabbreviations as used herein are defined below as follows:

When introducing elements of the present disclosure or the preferredembodiment(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

The term “and/or” when used in a list of two or more items, means thatany one of the listed items can be employed by itself or in combinationwith any one or more of the listed items. For example, the expression “Aand/or B” is intended to mean either or both of A and B, i.e. A alone, Balone or A and B in combination. The expression “A, B and/or C” isintended to mean A alone, B alone, C alone, A and B in combination, Aand C in combination, B and C in combination or A, B, and C incombination.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “between n₁ . . . and n₂” is used, where n₁ and n₂ are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety were the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon radical having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—), (—C::C—)].Examples of suitable alkenyl radicals include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether radical, wherein the term alkyl is as defined below.Examples of suitable alkyl ether radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl radical containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 8 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—) and ethylene (—CH₂CH₂—).Unless otherwise specified, the term “alkyl” may include “alkylene”groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) radical wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched chain hydrocarbon radical having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylradicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido”, “carboxamido”, and “carbamoyl,” as used herein, aloneor in combination, refer to an amino group as described below attachedto the parent molecular moiety through a carbonyl group, or vice versa.The term “C-amido” as used herein, alone or in combination, refers to a—C(O)N(RR′) group with R and R′ as defined herein or as defined by thespecifically enumerated “R” groups designated. The term “N-amido” asused herein, alone or in combination, refers to a RC(O)N(R′)— group,with R and R′ as defined herein or as defined by the specificallyenumerated “R” groups designated. The term “acylamino” as used herein,alone or in combination, embraces an acyl group attached to the parentmoiety through an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently chosen from hydrogen, alkyl,acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,any of which may themselves be optionally substituted. Additionally, Rand R′ may combine to form heterocycloalkyl, either of which may beoptionally substituted.

The term “aryl,” as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent radical C6H4=derived from benzene. Examplesinclude benzothiophene and benzimidazole.

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′, group-with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt. An “O-carboxy” group refers to a RC(O)O— group, where R is asdefined herein. A “C-carboxy” group refers to a —C(O)OR groups where Ris as defined herein.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein. In certain embodiments, said cycloalkyl will comprise from 5 to7 carbon atoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type. The latter type of isomer isexemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane,and bicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl radical having the meaning as defined above wherein one or morehydrogens are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkylradical, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the radical. Dihalo and polyhaloalkyl radicals may have two ormore of the same halo atoms or a combination of different halo radicals.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF2-), chloromethylene (—CHC1-) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or combinations thereof, fullysaturated or containing from 1 to 3 degrees of unsaturation, consistingof the stated number of carbon atoms and from one to three heteroatomschosen from N, O, and S, and wherein the N and S atoms may optionally beoxidized and the N heteroatom may optionally be quaternized. Theheteroatom(s) may be placed at any interior position of the heteroalkylgroup. Up to two heteroatoms may be consecutive, such as, for example,—CH2-NH—OCH3.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 15 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom chosenfrom N, O, and S. In certain embodiments, said heteroaryl will comprisefrom 1 to 4 heteroatoms as ring members. In further embodiments, saidheteroaryl will comprise from 1 to 2 heteroatoms as ring members. Incertain embodiments, said heteroaryl will comprise from 5 to 7 atoms.The term also embraces fused polycyclic groups wherein heterocyclicrings are fused with aryl rings, wherein heteroaryl rings are fused withother heteroaryl rings, wherein heteroaryl rings are fused withheterocycloalkyl rings, or wherein heteroaryl rings are fused withcycloalkyl rings. Examples of heteroaryl groups include pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl,indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated (but nonaromatic)monocyclic, bicyclic, or tricyclic heterocyclic group containing atleast one heteroatom as a ring member, wherein each said heteroatom maybe independently chosen from nitrogen, oxygen, and sulfur. In certainembodiments, said hetercycloalkyl will comprise from 1 to 4 heteroatomsas ring members. In further embodiments, said hetercycloalkyl willcomprise from 1 to 2 heteroatoms as ring members. In certainembodiments, said hetercycloalkyl will comprise from 3 to 8 ring membersin each ring. In further embodiments, said hetercycloalkyl will comprisefrom 3 to 7 ring members in each ring. In yet further embodiments, saidhetercycloalkyl will comprise from 5 to 6 ring members in each ring.“Heterocycloalkyl” and “heterocycle” are intended to include sulfones,sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclicfused and benzo fused ring systems; additionally, both terms alsoinclude systems where a heterocycle ring is fused to an aryl group, asdefined herein, or an additional heterocycle group. Examples ofheterocycle groups include aziridinyl, azetidinyl, 1,3-benzodioxolyl,dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl,dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl,benzothiazolyl, dihydroindolyl, dihy-dropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl,pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and thelike. The heterocycle groups may be optionally substituted unlessspecifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “in the main chain” refers to the longest contiguous oradjacent chain of carbon atoms starting at the point of attachment of agroup to the compounds of any one of the formulas disclosed herein.

The term “isocyanato” refers to a —NCO group.

The term “isothiocyanato” refers to a —NCS group.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms (i.e., C1-C6 alkyl).

The term “lower aryl,” as used herein, alone or in combination, meansphenyl or naphthyl, either of which may be optionally substituted asprovided.

The term “lower heteroaryl,” as used herein, alone or in combination,means either 1) monocyclic heteroaryl comprising five or six ringmembers, of which between one and four said members may be heteroatomschosen from N, O, and S, or 2) bicyclic heteroaryl, wherein each of thefused rings comprises five or six ring members, comprising between themone to four heteroatoms chosen from N, O, and S.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members(i.e., C3-C6 cycloalkyl). Lower cycloalkyls may be unsaturated. Examplesof lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomschosen from N, O, and S (i.e., C3-C6 heterocycloalkyl). Examples oflower heterocycloalkyls include pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lowerheterocycloalkyls may be unsaturated.

The term “lower amino,” as used herein, alone or in combination, refersto —NRR′, wherein R and R′ are independently chosen from hydrogen andlower alkyl, either of which may be optionally substituted.

The term “mercaptyl” as used herein, alone or in combination, refers toan RS— group, where R is as defined herein.

The term “nitro,” as used herein, alone or in combination, refers to—NO2.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer the —SO3H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)2-.

The term “N-sulfonamido” refers to a RS(O)2NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(O)2NRR′, group, with R and R′ asdefined herein.

The term “sulfonamido” encompasses both N-sulfonamido and S-sulfonamidogroups.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “thiocarbonyl,” as used herein, when alone includes thioformyl—C(S)H and in combination is a —C(S)— group.

The term “N-thiocarbamyl” refers to an ROC(S)NR′— group, with R and R′as defined herein.

The term “O-thiocarbamyl” refers to a —OC(S)NRR′, group with R and R′ asdefined herein.

The term “thiocyanato” refers to a —CNS group.

The term “trihalomethanesulfonamido” refers to a X3CS(O)2NR— group withX is a halogen and R as defined herein.

The term “trihalomethanesulfonyl” refers to a X3CS(O)2- group where X isa halogen.

The term “trihalomethoxy” refers to a X3CO— group where X is a halogen.

The term “trisubstituted silyl,” as used herein, alone or incombination, refers to a silicone group substituted at its three freevalences with groups as listed herein under the definition ofsubstituted amino. Examples include trimethysilyl,tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Wherestructurally feasible, two substituents may be joined together to form afused five-, six-, or seven-membered carbocyclic or heterocyclic ringconsisting of zero to three heteroatoms, for example formingmethylenedioxy or ethylenedioxy. An optionally substituted group may beunsubstituted (e.g., —CH2CH3), fully substituted (e.g., —CF2CF3),monosubstituted (e.g., —CH2CH2F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH2CF3). Wheresubstituents are recited without qualification as to substitution, bothsubstituted and unsubstituted forms are encompassed. Where a substituentis qualified as “substituted,” the substituted form is specificallyintended. Additionally, different sets of optional substituents to aparticular moiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety chosen fromhydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl andheterocycloalkyl, any of which may be optionally substituted. Such R andR′ groups should be understood to be optionally substituted as definedherein. Whether an R group has a number designation or not, every Rgroup, including R, R′ and Rn where n=(1, 2, 3, . . . n), everysubstituent, and every term should be understood to be independent ofevery other in terms of selection from a group. Should any variable,substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more thanone time in a formula or generic structure, its definition at eachoccurrence is independent of the definition at every other occurrence.Those of skill in the art will further recognize that certain groups maybe attached to a parent molecule or may occupy a position in a chain ofelements from either end as written. For example, an unsymmetrical groupsuch as —C(O)N(R)— may be attached to the parent moiety at either thecarbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and 1-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A dashed line between two atoms in a drawing of amolecule indicates that an additional bond may be present or absent atthat position.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder,”“syndrome,” and “condition” (as in medical condition), in that allreflect an abnormal condition of the human or animal body or of one ofits parts that impairs normal functioning, is typically manifested bydistinguishing signs and symptoms, and causes the human or animal tohave a reduced duration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

The term “MCT4 inhibitor” is used herein to refer to a compound thatexhibits an IC50 with respect to MCT4 activity of no more than about 100μM and more typically not more than about 50 μM, as measured in the MCT4enzyme assay described generally herein below. IC50 is thatconcentration of inhibitor that reduces the activity of an enzyme (e.g.,MCT4) to half-maximal level. Certain compounds disclosed herein havebeen discovered to exhibit inhibition against MCT4. In certainembodiments, compounds will exhibit an IC50 with respect to MCT4 of nomore than about 10 μM; in further embodiments, compounds will exhibit anIC50 with respect to MCT4 of no more than about 5 μM; in yet furtherembodiments, compounds will exhibit an IC50 with respect to MCT4 of notmore than about 1 μM; in yet further embodiments, compounds will exhibitan IC50 with respect to MCT4 of not more than about 200 nM, as measuredin the MCT4 binding assay described herein.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder oron the effecting of a clinical endpoint.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without undue toxicity,irritation, and allergic response, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. Treatment may also be preemptive in nature, i.e.,it may include prevention of disease. Prevention of a disease mayinvolve complete protection from disease, for example as in the case ofprevention of infection with a pathogen, or may involve prevention ofdisease progression. For example, prevention of a disease may not meancomplete foreclosure of any effect related to the diseases at any level,but instead may mean prevention of the symptoms of a disease to aclinically significant or detectable level. Prevention of diseases mayalso mean prevention of progression of a disease to a later stage of thedisease.

The term “patient” is generally synonymous with the term “subject” andincludes all mammals including humans. Examples of patients includehumans, livestock such as cows, goats, sheep, pigs, and rabbits, andcompanion animals such as dogs, cats, rabbits, and horses. Preferably,the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present invention includes compounds listed above in the formof salts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N′-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation. Accordingly, provided herein arepharmaceutical formulations which comprise one or more of certaincompounds disclosed herein, or one or more pharmaceutically acceptablesalts, esters, prodrugs, amides, or solvates thereof, together with oneor more pharmaceutically acceptable carriers thereof and optionally oneor more other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. The pharmaceutical compositionsdisclosed herein may be manufactured in any manner known in the art,e.g., by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds may be administered orally or via injection at a dose of from0.1 to 500 mg/kg per day. The dose range for adult humans is generallyfrom 5 mg to 2 g/day. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of one or morecompounds which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds can be administered in various modes, e.g. orally,topically, or by injection. The precise amount of compound administeredto a patient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof) in combination with another therapeuticagent. By way of example only, if one of the side effects experienced bya patient upon receiving one of the compounds herein is hypertension,then it may be appropriate to administer an anti-hypertensive agent incombination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit of experienced by a patient may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. By way of example only, in a treatment for diabetes involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the patient withanother therapeutic agent for diabetes. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

Thus, in another aspect, certain embodiments provide methods fortreating MCT4-mediated disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound disclosed herein effective to reduce or prevent said disorderin the subject, in combination with at least one additional agent forthe treatment of said disorder that is known in the art. In a relatedaspect, certain embodiments provide therapeutic compositions comprisingat least one compound disclosed herein in combination with one or moreadditional agents for the treatment of MCT4-mediated disorders.

Also provided herein is a method of treating a monocarboxylatetransporter MCT4-mediated disorder in a subject in need thereof,comprising the sequential or co-administration of a compound asdisclosed herein or a pharmaceutically acceptable salt thereof, andanother therapeutic agent.

In certain embodiments, the therapeutic agent is a protein kinaseinhibitor.

In certain embodiments, the protein kinase inhibitor is chosen fromAurora B, EGFR, PLK-1, CDKs inhibitors.

In certain embodiments, the therapeutic agent is chosen from anantimetabolite, bcr-abl inhibitor, DNA damaging agent, EGFR inhibitor,microtubule stabilizing inhibitor, mitotic arrest inhibitor, S-phaseinhibitor, and a taxane.

In certain embodiments, the therapeutic agent is a DNA damaging agentchosen from an alkylating agent, anthracycline, antimetabolite agent,crosslinking agent, DNA replication inhibitor, intercalator, microtubuledisruptor, PARP inhibitor, radiomimetic agent, radiosensitizer, strandbreak agent, and topoisomerase II inhibitor.

In certain embodiments, the therapeutic agent is chosen fromaminoglutethimide, amsacrine, anastrozole, asparaginase, barasertib,bcg, bicalutamide, bleomycin, buserelin, busulfan, campothecin,capecitabine, carboplatin, carmustine, chlorambucil, chloroquine,cisplatin, cladribine, clodronate, colchicine, cyclophosphamide,cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin,demethoxyviridin, dichloroacetate, dienestrol, diethylstilbestrol,docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide,everolimus, exemestane, filgrastim, fludarabine, fludrocortisone,fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein,goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon,irinotecan, ironotecan, letrozole, leucovorin, leuprolide, levamisole,lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol,melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin,mitotane, mitoxantrone, nilutamide, nocodazole, olaparib, octreotide,oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine,plicamycin, porfimer, procarbazine, raltitrexed, rituximab, sorafenib,streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus,teniposide, testosterone, thioguanine, thiotepa, titanocene dichloride,topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine,and vinorelbine.

For use in cancer and neoplastic diseases a MCT4 inhibitor may beoptimally used together with one or more of the following non-limitingexamples of anti-cancer agents: (1) alkylating agents, including but notlimited to cisplatin (PLATIN), carboplatin (PARAPLATIN), oxaliplatin(ELOXATIN), streptozocin (ZANOSAR), busulfan (MYLERAN) andcyclophosphamide (ENDOXAN); (2) anti-metabolites, including but notlimited to mercaptopurine (PURINETHOL), thioguanine, pentostatin(NIPENT), cytosine arabinoside (ARA-C), gemcitabine (GEMZAR),fluorouracil (CARAC), leucovorin (FUSILEV) and methotrexate(RHEUMATREX); (3) plant alkaloids and terpenoids, including but notlimited to vincristine (ONCOVIN), vinblastine and paclitaxel (TAXOL);(4) topoisomerase inhibitors, including but not limited to irinotecan(CAMPTOSAR), topotecan (HYCAMTIN) and etoposide (EPOSIN); (5) cytotoxicantibiotics, including but not limited to actinomycin D (COSMEGEN),doxorubicin (ADRIAMYCIN), bleomycin (BLENOXANE) and mitomycin (MITOSOL);(6) angiogenesis inhibitors, including but not limited to sunitinib(SUTENT) and bevacizumab (AVASTIN); and (7) tyrosine kinase inhibitors,including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA),lapatininb (TYKERB) and axitinib (INLYTA).

Where a subject is suffering from or at risk of suffering from aninflammatory condition, a MCT4 inhibitor compound described herein isoptionally used together with one or more agents or methods for treatingan inflammatory condition in any combination. Therapeuticagents/treatments for treating an autoimmune and/or inflammatorycondition include, but are not limited to any of the following examples:(1) corticosteroids, including but not limited to cortisone,dexamethasone, and methylprednisolone; (2) nonsteroidalanti-inflammatory drugs (NSAIDs), including but not limited toibuprofen, naproxen, acetaminophen, aspirin, fenoprofen (NALFON),flurbiprofen (ANSAID), ketoprofen, oxaprozin (DAYPRO), diclofenac sodium(VOLTAREN), diclofenac potassium (CATAFLAM), etodolac (LODINE),indomethacin (INDOCIN), ketorolac (TORADOL), sulindac (CLINORIL),tolmetin (TOLECTIN), meclofenamate (MECLOMEN), mefenamic acid (PONSTEL),nabumetone (RELAFEN) and piroxicam (FELDENE); (3) immunosuppressants,including but not limited to methotrexate (RHEUMATREX), leflunomide(ARAVA), azathioprine (IMURAN), cyclosporine (NEORAL, SANDIMMUNE),tacrolimus and cyclophosphamide (CYTOXAN); (4) CD20 blockers, includingbut not limited to rituximab (RITUXAN); (5) Tumor Necrosis Factor (TNF)blockers, including but not limited to etanercept (ENBREL), infliximab(REMICADE) and adalimumab (HUMIRA); (6) interleukin-1 receptorantagonists, including but not limited to anakinra (KINERET); (7)interleukin-6 inhibitors, including but not limited to tocilizumab(ACTEMRA); (8) interleukin-17 inhibitors, including but not limited toAIN457; (9) Janus kinase inhibitors, including but not limited totasocitinib; and (10) syk inhibitors, including but not limited tofostamatinib.

In certain embodiments, the method further comprises administeringnon-chemical methods of cancer treatment.

In certain embodiments, the method further comprises administeringradiation therapy.

In certain embodiments, the method further comprises administeringsurgery, thermoablation, focused ultrasound therapy, cryotherapy, or anycombination thereof.

In any case, the multiple therapeutic agents (at least one of which is acompound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Thus, in another aspect, certain embodiments provide methods fortreating MCT4-mediated disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound disclosed herein effective to reduce or prevent said disorderin the subject, in combination with at least one additional agent forthe treatment of said disorder that is known in the art. In a relatedaspect, certain embodiments provide therapeutic compositions comprisingat least one compound disclosed herein in combination with one or moreadditional agents for the treatment of MCT4-mediated disorders.

The present disclosure provides compounds and pharmaceuticalcompositions that inhibit glutaminase activity, particularly MCT4activity and are thus useful in the treatment or prevention of disordersassociated with MCT4. Compounds and pharmaceutical compositions of thepresent disclosure selectively modulate MCT4 and are thus useful in thetreatment or prevention of a range of disorders associated with MCT4 andinclude, but are not limited to, proliferative and inflammatorydiseases.

Accordingly, provided herein is a method for inhibiting activity of themonocarboxylate transporter MCT4, or a mutant thereof, in a biologicalsample comprising the step of contacting said biological sample with acompound as disclosed herein, or a salt thereof.

Also provided herein is a method for inhibiting activity of themonocarboxylate transporter MCT4, or a mutant thereof, in a patientcomprising the step of administering to the patient a compound asdisclosed herein, or a salt thereof.

Also provided herein is a method for selectively inhibiting activity ofthe monocarboxylate transporter MCT4, or a mutant thereof, over themonocarboxylate transporter MCT1, or a mutant thereof, in a patientcomprising the step of administering to the patient a compound asdisclosed herein, or a salt thereof.

In certain embodiments, the inhibition is at least 100-fold selectivefor MCT4 over MCT1.

In certain embodiments, the compounds and pharmaceutical compositions ofthe present disclosure may be useful in the treatment or prevention ofcancer.

In certain embodiments, the compounds of the present disclosure may beused to prevent or treat cancer, wherein the cancer is one or a variantof Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML),Adrenocortical Carcinoma, AIDS-Related Cancers (Kaposi Sarcoma andLymphoma), Anal Cancer, Appendix Cancer, Atypical Teratoid/RhabdoidTumor, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic),Bladder Cancer, Bone Cancer (including Osteosarcoma and MalignantFibrous Histiocytoma), Brain Tumor (such as Astrocytomas, Brain andSpinal Cord Tumors, Brain Stem Glioma, Central Nervous System AtypicalTeratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors,Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma,Medulloepithelioma, Pineal Parenchymal Tumors of IntermediateDifferentiation, Supratentorial Primitive Neuroectodermal Tumors andPineoblastoma), Breast Cancer, Bronchial Tumors, Burkitt Lymphoma,Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System(such as Atypical Teratoid/Rhabdoid Tumor, Embryonal Tumors andLymphoma), Cervical Cancer, Childhood Cancers, Chordoma, ChronicLymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), ChronicMyeloproliferative Disorders, Colon Cancer, Colorectal Cancer,Craniopharyngioma, Cutaneous T-Cell Lymphoma (Mycosis Fungoides andSézary Syndrome), Duct, Bile (Extrahepatic), Ductal Carcinoma In Situ(DCIS), Embryonal Tumors (Central Nervous System), Endometrial Cancer,Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma,Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor,Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer(like Intraocular Melanoma, Retinoblastoma), Fibrous Histiocytoma ofBone (including Malignant and Osteosarcoma) Gallbladder Cancer, Gastric(Stomach) Cancer, Gastrointestinal Carcinoid Tumor, GastrointestinalStromal Tumors (GIST), Germ Cell Tumor (Extracranial, Extragonadal,Ovarian), Gestational Trophoblastic Tumor, Glioma, Hairy Cell Leukemia,Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer,Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer,Intraocular Melanoma, Islet Cell Tumors (Endocrine, Pancreas), KaposiSarcoma, Kidney (including Renal Cell), Langerhans Cell Histiocytosis,Laryngeal Cancer, Leukemia (including Acute Lymphoblastic (ALL), AcuteMyeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous (CML),Hairy Cell), Lip and Oral Cavity Cancer, Liver Cancer (Primary), LobularCarcinoma In Situ (LCIS), Lung Cancer (Non-Small Cell and Small Cell),Lymphoma (AIDS-Related, Burkitt, Cutaneous T-Cell (Mycosis Fungoides andSézary Syndrome), Hodgkin, Non-Hodgkin, Primary Central Nervous System(CNS), Macroglobulinemia, Waldenström, Male Breast Cancer, MalignantFibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma,Medulloepithelioma, Melanoma (including Intraocular (Eye)), Merkel CellCarcinoma, Mesothelioma (Malignant), Metastatic Squamous Neck Cancerwith Occult Primary, Midline Tract Carcinoma Involving NUT Gene, MouthCancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/PlasmaCell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes,Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia,Chronic (CML), Myeloid Leukemia, Acute (AML), Myeloma and MultipleMyeloma, Myeloproliferative Disorders (Chronic), Nasal Cavity andParanasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma,Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, OralCavity Cancer, Lip and, Oropharyngeal Cancer, Osteosarcoma and MalignantFibrous Histiocytoma of Bone, Ovarian Cancer (such as Epithelial, GermCell Tumor, and Low Malignant Potential Tumor), Pancreatic Cancer(including Islet Cell Tumors), Papillomatosis, Paraganglioma, ParanasalSinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer,Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors ofIntermediate Differentiation, Pineoblastoma and Supratentorial PrimitiveNeuroectodermal Tumors, Pituitary Tumor, Plasma Cell Neoplasm/MultipleMyeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, PrimaryCentral Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer,Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Transitional CellCancer, Retinoblastoma, Rhabdomyo sarcoma, Salivary Gland Cancer,Sarcoma (like Ewing Sarcoma Family of Tumors, Kaposi, Soft Tissue,Uterine), Sézary Syndrome, Skin Cancer (such as Melanoma, Merkel CellCarcinoma, Nonmelanoma), Small Cell Lung Cancer, Small Intestine Cancer,Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer withOccult Primary, Metastatic, Stomach (Gastric) Cancer, SupratentorialPrimitive Neuroectodermal Tumors, T-Cell Lymphoma (Cutaneous, MycosisFungoides and Sézary Syndrome), Testicular Cancer, Throat Cancer,Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancerof the Renal Pelvis and Ureter, Trophoblastic Tumor (Gestational),Unknown Primary, Unusual Cancers of Childhood, Ureter and Renal Pelvis,Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial,Uterine Sarcoma, Waldenström Macroglobulinemia or Wilms Tumor.

In certain embodiments, the cancer to be treated is one specific toT-cells such as T-cell lymphoma and lymphoblastic T-cell leukemia.

In certain embodiments, methods described herein are used to treat adisease condition comprising administering to a subject in need thereofa therapeutically effective amount of a compound of Formula I orpharmaceutically acceptable salt thereof, wherein the condition iscancer which has developed resistance to chemotherapeutic drugs and/orionizing radiation.

In certain embodiments, the compounds and pharmaceutical compositions ofthe present disclosure may be useful in the treatment or prevention ofan inflammatory disease.

In certain embodiments, the compounds of the present disclosure may beused to prevent or treat inflammatory disease, wherein the inflammatorydisease is one or a variant of acid-induced lung injury, acne (PAPA),acute respiratory distress syndrome, Addison's disease, adrenalhyperplasia, adrenocortical insufficiency, ageing, AIDS, alcoholichepatitis, alcoholic liver disease, allergen induced asthma, allergicbronchopulmonary aspergillosis, allergic conjunctivitis, alopecia,Alzheimer's disease, amyloidosis, amyotrophic lateral sclerosis, anginapectoris, angioedema, anhidrotic ectodermal dysplasia (e.g. with immunedeficiency), ankylosing spondylitis, anterior segment inflammation,antiphospholipid syndrome, aphthous stomatitis, appendicitis, asthma,atherosclerosis, atopic dermatitis, autoimmune diseases, autoimmunehepatitis, bee sting-induced inflammation, Behcet's disease, Bell'sPalsy, berylliosis, Blau syndrome, bone pain, bronchiolitis, burns,bursitis, cardiac hypertrophy, carpal tunnel syndrome, catabolicdisorders, cataracts, cerebral aneurysm, chemical irritant-inducedinflammation, chorioretinitis, chronic heart failure, chronic lungdisease of prematurity, chronic obstructive pulmonary disease, colitis,complex regional pain syndrome, connective tissue disease, cornealulcer, Crohn's disease, cryopyrin-associated periodic syndromes,cryptococcosis, cystic fibrosis, deficiency of theinterleukin-1-receptor antagonist, dermatitis, dermatitis endotoxemia,dermatomyositis, endometriosis, endotoxemia, epicondylitis,erythroblastopenia, familial amyloidotic polyneuropathy, familial coldurticaria, familial Mediterranean fever, fetal growth retardation,glaucoma, glomerular disease, glomerular nephritis, gout, goutyarthritis, graft-versus-host disease, gut diseases, head injury,headache, hearing loss, heart disease, hemolytic anemia, Henoch-Scholeinpurpura, hepatitis, hereditary periodic fever syndrome, herpes zosterand simplex, HIV-1, Huntington's disease, hyaline membrane disease,hyperammonemia, hypercalcemia, hypercholesterolemia,hyperimmunoglobulinemia D with recurrent fever, hypoplastic and otheranemias, idiopathic pulmonary fibrosis, idiopathic thrombocytopenicpurpura, incontinentia pigmenti, infectious mononucleosis, inflammatorybowel disease, inflammatory lung disease, inflammatory neuropathy,inflammatory pain, insect bite-induced inflammation, iritis,ischemia/reperfusion, juvenile rheumatoid arthritis, keratitis, kidneydisease, kidney injury caused by parasitic infections, kidney transplantrejection prophylaxis, leptospirosis, Loeffler's syndrome, lung injury,lupus, lupus nephritis, meningitis, mesothelioma, mixed connectivetissue disease, Muckle-Wells syndrome (urticaria deafness amyloidosis),multiple sclerosis, muscle wasting, muscular dystrophy, myastheniagravis, myocarditis, mycosis fungoides, myelodysplastic syndrome,myositis, nasal sinusitis, necrotizing enterocolitis, neonatal onsetmultisystem inflammatory disease (NOMID), nephrotic syndrome, neuritis,neuropathological diseases, non-allergen induced asthma, obesity, ocularallergy, optic neuritis, organ transplant, osteoarthritis, otitis media,Paget's disease, pain, pancreatitis, Parkinson's disease, pemphigus,pericarditis, periodic fever, periodontitis, pertussis, perineal orperitoneal endometriosis, pharyngitis and adenitis (PFAPA syndrome),plant irritant-induced inflammation, pneumocystis infection, pneumonia,pneumonitis, poison ivy/urushiol oil-induced inflammation, polyarteritisnodosa, polychondritis, polycystic kidney disease, polymyositis,psoriasis, psychosocial stress disease, pulmonary disease, pulmonaryfibrosis, pulmonary hypertension, pyoderma gangrenosum, pyogenic sterilearthritis, renal disease, retinal disease, rheumatic disease, rheumatoidarthritis, rheumatic carditis, sarcoidosis, sebborrhea, sepsis, severepain, sickle cell, sickle cell anemia, silica-induced diseases,Sjogren's syndrome, skin diseases, sleep apnea, spinal cord injury,Stevens-Johnson syndrome, stroke, subarachnoid hemorrhage, sunburn,systemic sclerosis (scleroderma), temporal arteritis, tenosynovitis,thrombocytopenia, thyroiditis, tissue transplant, TNF receptorassociated periodic syndrome (TRAPS), Toxoplasmosis, transplant,traumatic brain injury, tuberculosis, type 1 diabetes, type 2 diabetes,ulcerative colitis, urticaria, uveitis, Wegener's granulomatosis, andweight loss.

Thus, in another aspect, certain embodiments provide methods fortreating a monocarboxylate transporter MCT4-mediated disorder in asubject in need thereof, comprising the step of administering to saidpatient a compound as disclosed herein, or a pharmaceutically acceptablesalt thereof.

In certain embodiments, the subject is a human.

In certain embodiments, the moncarboxylate transporter MCT4-mediateddisorder is chosen from an inflammatory disorder and a proliferativedisorder.

In certain embodiments, the moncarboxylate transporter MCT4-mediateddisorder is a proliferative disorder.

In certain embodiments, the proliferative disorder is cancer.

In certain embodiments, the cancer is chosen from adenocarcinoma, adultT-cell leukemia/lymphoma, bladder cancer, blastoma, bone cancer, breastcancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer,colorectal cancer, esophageal cancer, gastrointestinal cancer,glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer,head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma,intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lungcancer, lymphoma, liver cancer, small cell lung cancer, non-small celllung cancer, mesothelioma, multiple myeloma, ocular cancer, optic nervetumor, oral cancer, ovarian cancer, pituitary tumor, primary centralnervous system lymphoma, prostate cancer, pancreatic cancer, pharyngealcancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer,spinal tumor, small intestine cancer, stomach cancer, T-cell lymphoma,testicular cancer, thyroid cancer, throat cancer, urogenital cancer,urothelial carcinoma, uterine cancer, vaginal cancer, and Wilms' tumor.

In certain embodiments, the moncarboxylate transporter MCT4-mediateddisorder is an inflammatory disorder.

In certain embodiments, the inflammatory disorder is chosen from Crohn'sdisease, ulcerative colitis, idiopathic pulmonary fibrosis, musculardystrophy, rheumatoid arthritis, and systemic sclerosis (scleroderma).

Also provided herein is a compound as disclosed herein, or apharmaceutically acceptable salt thereof, for use in human therapy.

Also provided herein is a compound as disclosed herein, or apharmaceutically acceptable salt thereof, for use in treating amonocarboxylate transporter MCT4-mediated disorder, for example asdisclosed in any of the embodiments and paragraphs above pertaining tomethods of treatment.

Also provided herein is the use of a compound as disclosed herein, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament to treat a monocarboxylate transporter MCT4-mediateddisorder, for example as disclosed in any of the embodiments andparagraphs above pertaining to methods of treatment.

Metabolic syndrome (also known as metabolic syndrome X) is characterizedby having at least three of the following symptoms: insulin resistance;abdominal fat—in men this is defined as a 40 inch waist or larger, inwomen 35 inches or larger; high blood sugar levels—at least 110milligrams per deciliter (mg/dL) after fasting; high triglycerides—atleast 150 mg/dL in the blood stream; low HDL-less than 40 mg/dL;pro-thrombotic state (e.g. high fibrinogen or plasminogen activatorinhibitor in the blood); or blood pressure of 130/85 mmHg or higher. Aconnection has been found between metabolic syndrome and otherconditions such as obesity, high blood pressure and high levels of LDLcholesterol, all of which are risk factors for cardiovascular diseases.For example, an increased link between metabolic syndrome andatherosclerosis has been shown. People with metabolic syndrome are alsomore prone to developing type 2 diabetes, as well as PCOS (polycysticovarian syndrome) in women and prostate cancer in men.

As described above, insulin resistance can be manifested in severalways, including type 2 diabetes. Type 2 diabetes is the condition mostobviously linked to insulin resistance. Compensatory hyperinsulinemiahelps maintain normal glucose levels-often for decades, before overtdiabetes develops. Eventually the beta cells of the pancreas are unableto overcome insulin resistance through hypersecretion. Glucose levelsrise, and a diagnosis of diabetes can be made. Patients with type 2diabetes remain hyperinsulinemic until they are in an advanced stage ofdisease. As described above, insulin resistance can also correlate withhypertension. One half of patients with essential hypertension areinsulin resistant and hyperinsulinemic, and there is evidence that bloodpressure is linked to the degree of insulin resistance. Hyperlipidemia,too, is associated with insulin resistance. The lipid profile ofpatients with type 2 diabetes includes increased serum very-low-densitylipoprotein cholesterol and triglyceride levels and, sometimes, adecreased low-density lipoprotein cholesterol level. Insulin resistancehas been found in persons with low levels of high-density lipoprotein.Insulin levels have also been linked to very-low-density lipoproteinsynthesis and plasma triglyceride levels.

Accordingly, also disclosed are methods of treating insulin resistancein a subject comprising selecting a subject in need of treatment forinsulin resistance; and administering to the subject an effective amountof a compound that inhibits MCT4.

Specific diseases to be treated by the compounds, compositions, andmethods disclosed herein are those mediated at least in part by MCT4.Accordingly, disclosed herein are methods: for reducing glycogenaccumulation in a subject; for raising HDL or HDLc, lowering LDL orLDLc, shifting LDL particle size from small dense to normal LDL,lowering VLDL, lowering triglycerides, or inhibiting cholesterolabsorption in a subject; for reducing insulin resistance, enhancingglucose utilization or lowering blood pressure in a subject; forreducing visceral fat in a subject; for reducing serum transaminases ina subject; or for treating disease; all comprising the administration ofa therapeutic amount of a compound as described herein, to a patient inneed thereof. In further embodiments, the disease to be treated may be ametabolic disease. In further embodiment, the metabolic disease may beselected from the group consisting of: obesity, diabetes melitus,especially Type 2 diabetes, hyperinsulinemia, glucose intolerance,metabolic syndrome X, dyslipidemia, hypertriglyceridemia,hypercholesterolemia, and hepatic steatosis. In other embodiments, thedisease to be treated may be selected from the group consisting of:cardiovascular diseases including vascular disease, atherosclerosis,coronary heart disease, cerebrovascular disease, heart failure andperipheral vessel disease. In preferred embodiments, the methods abovedo not result in the induction or maintenance of a hypoglycemic state.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

List of Abbreviations

Ac₂O=acetic anhydride; AcCl=acetyl chloride; AcOH=acetic acid;AIBN=azobisisobutyronitrile; aq.=aqueous;BAST=bis(2-methoxyethyl)aminosulfur trifluoride;BCECF=2′,7′-bis-(carboxyethyl)-5(6)-carboxyfluorescein; Bu=butyl;Bu₃SnH=tributyltin hydride; CD₃OD=deuterated MeOH; CDCl₃=deuteratedchloroform; CDI=1,1′-carbonyldiimidazole; DAST=(diethylamino)sulfurtrifluoride; dba=dibenzylideneacetone;DBU=1,8-diazabicyclo[5.4.0]undec-7-ene; DCM=dichloromethane;DEAD=diethyl azodicarboxylate; DIAD=diisopropyl azodicarboxylate;DIBAL-H=di-iso-butyl aluminium hydride;DIEA=DIPEA=N,N-diisopropylethylamine; DMAP=4-dimethylaminopyridine;DMF=N,N-dimethylformamide; DMSO-d₆=deuterated dimethyl sulfoxide;DMSO=dimethyl sulfoxide; DPPA=diphenylphosphoryl azide;dppf=1,1′-bis(diphenylphosphino)ferrocene;EDC.HCl=EDCI.HCl=1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride; Et=ethyl; Et₂O=diethyl ether; EtOAc=ethyl acetate;EtOH=ethanol; h=hour;HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate methanaminium; HMDS=hexamethyldisilazane;HOBT=1-hydroxybenzotriazole; i-Pr=isopropyl=2-propyl;i-PrOH=isopropanol; LAH=lithium aluminium hydride; LDA=lithiumdiisopropyl amide; LiHMDS=Lithium bis(trimethylsilyl)amide;MeCN=acetonitrile; MeI=methyl iodide; MeOH=MeOH; MP-carbonateresin=macroporous triethylammonium methylpolystyrene carbonate resin;MsCl=mesyl chloride; MTBE=methyl tertiary butyl ether;n-BuLi=n-butyllithium; NaHMDS=sodium bis(trimethylsilyl)amide;NaOEt=sodium ethoxide; NaOMe=sodium methoxide; NaOtBu=sodium t-butoxide;NBS=N-bromosuccinimide; NCS=N-chlorosuccinimide; NIS=N-iodosuccinimide;NMP=N-Methyl-2-pyrrolidone;Pd(PPh3)4=tetrakis(triphenylphosphine)-palladium(0);Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium(0);PdCl₂(PPh₃)₂=bis(triphenylphosphine)palladium(II) dichloride;PG=protecting group; Ph=phenyl; prep-HPLC=preparative high-performanceliquid chromatography; PMB=para-methoxybenzyl; PMBCl=para-methoxybenzylchloride; PMBOH=para-methoxybenzyl alcohol;PyBop=(benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate; Pyr=pyridine; RT=room temperature;RuPhos=2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl;sat.=saturated; ss=saturated solution;tBu=t-Bu=tert-butyl=1,1-dimethylethyl; TBAF=tetrabutylammonium fluoride;TBDPS=t-butyldiphenylsilyl; t-BuOH=tert-butanol; T3P=PropylphosphonicAnhydride; TEA=Et₃N=triethylamine; TFA=trifluoroacetic acid;TFAA=trifluoroacetic anhydride; THF=tetrahydrofuran;TIPS=triisopropylsilyl; Tot=toluene; TsCl=tosyl chloride;Trt=trityl=(triphenyl)methyl;Xantphos=4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene;XPhos=2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

General Synthetic Methods for Preparing Compounds

The following schemes can be used to practice the present invention.

A general, but not intended to be limiting, synthetic scheme for theexamples in this disclosure is depicted in Scheme I. An appropriatelysubstituted 2,4-diketobutanoic ester is reacted with a substitutedhydrazine to form the pyrazole core. Reduction of the ester gives ahydroxymethyl compound. The side chain can be completed by directalkylation with a 2-haloester, as shown in pathway (a). Alternatively,the hydroxymethyl functionality is converted to a halomethyl group,which can undergo displacement with a 2-hydroxyester, as shown inpathway (b), or be transformed via Wittig chemistry, as shown in pathway(c) to given an alkene.

Scheme II, depicted above, may be use to prepare certain examplesdisclosed herein. In step (a), organohalide 201 is converted to anorganolithium, followed by condensation with the substituted acetamideto give acetyl functionalized compound 202. This compound is reacted instep (b) under Claisen conditions with an oxalate ester to give2,4-diketoester 203, which is then reacted with a substituted hydrazinein step (c) to construct the pyrazole core of 204. The esterfunctionality is reduced in step (d), and in step (e) the resultingalcohol 205 is alkylated with an appropriate haloacetate ester,affording ether 206. Finally, the ester is hydrolyzed in step (f) underbasic conditions to give carboxylic acid 207. In the scheme as depicted,R₁₀₀-R₁₀₃ will be understood by one of skill in the art to be anyappropriate group. For example, in certain embodiments, R₁₀₀ and R₁₀₁may be independently chosen from aryl, cycloalkyl, heterocycloalkyl, andheteroaryl, any of which is optionally substituted. Likewise, in certainembodiments, R₁₀₂ and R₁₀₃ may be independently chosen from hydrogen,alkyl, and halogen. R₁₀₀-R₁₀₃ may also correspond to the groups definedin Formula I, II, or any other formula disclosed herein. Finally, thisscheme may be joined at any point by employing a suitable intermediateshown herein that is available either from commercial sources oralternate synthetic methods.

Scheme III, depicted above, can be used to prepare certain examplecompounds disclosed herein. Steps (a)-(d) from Scheme I are used toobtain pyrazolemethanol 301, which is then converted to bromomethylcompound 302 in step (e), using one of various techniques available forthis transformation. Alkyl halide 302 is then reacted under Williamsonether conditions with a hydroxyester in step (f), to give 303. Synthesisis then completed in step (g) by ester hydrolysis to 304.

Scheme IV, depicted above, can be utilized for certain example compoundsdisclosed herein. Steps (a)-(d) from Scheme I are used to obtainpyrazolemethanol 401, which is alkylated to give tBu ester 402. Cleavageof the ester is accomplished under acidic conditions, to give acid 403.

Scheme V, depicted above, can be utilized for certain example compoundsdisclosed herein. Steps (a)-(e) from Scheme III are used to obtain(bromomethyl)pyrazole 501. Reaction with a hydroxyester under basicconditions gives tBu ester 502. Cleavage of the ester is accomplishedunder acidic conditions, to give acid 503.

Scheme VI, depicted above, may be use to prepare certain examplecompounds disclosed herein. Phenylacetone is condensed with oxalateester to give the 5-phenylpentanoate ester 601. Condensation withsubstituted hydrazine forms the pyrazole core of 602. Ester reduction,alcohol alkylation, and ester hydrolysis proceeds as before. Synthesisof acid 603 is completed by either using steps (d)-(f) from Scheme II,or steps (d)-(g) from Scheme III.

Scheme VII, depicted above, can be used to prepare certain examplecompounds disclosed herein. Acetylated hydroxyaryl compound 701 reactsunder Williamson ether conditions with an alkyl halide or similarcompound, giving alkoxyaryl compound 702. Condensation with oxalateester gives a 2,4-diketoester 703, as in Scheme II. Synthesis iscompleted by either using steps (d)-(f) from Scheme II, or steps (d)-(g)from Scheme III.

Scheme VIII, depicted above, can be used to synthesize certain examplecompounds disclosed herein. Bromoaryl compound 801 is converted tomethoxyaryl compound 802 in the presence of a suitable metal catalyst inthe presence of base. The methyl ether is cleaved with a Lewis acid. Theresulting hydroxyl compound is reacted under Williamson ether conditionsto give alkoxyaryl compound 803. Alternatively, the bromoaryl compoundis reacted directly with an alcohol of interest to afford the desiredether 803 directly. In the scheme as depicted, R₁₀₀-R₁₀₆ will beunderstood by one of skill in the art to be any appropriate group.Synthesis of 804 is completed by either using steps (c)-(f) from SchemeII, or steps (c)-(g) from Scheme III.

Scheme IX, depicted above, can be used to synthesize certain examplecompounds disclosed herein. Bromoaryl compound 901 is converted to the(bromomethyl) pyrazole 904. The compound is reacted under Williamsonether conditions with a suitable glycolic ester to give ether 905.Transesterification to the methyl ester 905 is followed by displacementof the aryl bromide using an appropriate Pd⁰ catalyst. Synthesis iscompleted by basic hydrolysis of the methyl ester, affording acid 906.

Scheme X, depicted above, can be used to synthesize certain examplecompounds disclosed herein. Chloroaryl carboxylic ester 1001 is coupledwith an organozinc reagent in the presence of copper(I) iodide to give1002. The ester functionality is converted to methyl ketone 1003.Condensation with diethyl oxalate gives the □-diketone compound.Synthesis of 1004 is completed by either using steps (c)-(f) from SchemeII, or steps (c)-(g) from Scheme III.

Scheme XI, depicted above, can be used to synthesize certain examplecompounds disclosed herein. Pyrazole ester 1101 is obtained via steps(a)-(c) of Scheme II. The compound is coupled under Mitsunobu conditionswith an appropriate alcohol to give alkylated product 1102. Synthesis ofacid 1103 is completed by either using steps (d)-(f) from Scheme II, orsteps (d)-(g) from Scheme III.

Scheme XII, depicted above, can be used to synthesize certain examplecompounds disclosed herein. Pyrazole ester 1201 is obtained via steps(a)-(c) of Scheme II. The compound is coupled with an alkyl halide inthe presence of base to give 1202. Synthesis of acid 1203 is completedby either using steps (d)-(f) from Scheme II, or steps (d)-(g) fromScheme III.

Scheme XIII, depicted above, may be used to prepared certain examplecompounds disclosed herein. A 2,4-diketoester is condensed with anitroaromatic compound, such as 4-nitroaniline, to give pyrazole moiety1301. Reduction of the nitro group is followed by reductive amination togive a (dialkyl)amino compound 1302. Synthesis of acid 1303 is completedby either using steps (d)-(f) from Scheme II, or steps (d)-(g) fromScheme III.

Scheme XIV, depicted above, can be used to synthesize certain examplecompounds disclosed herein. A 2,4-diketoester is condensed withhydrazine to form pyrazole 1401, which is then alkylated with asubstituted benzyl bromide to afford 1402. Reduction to the amine isfollowed by reductive alkylation to give substituted amine 1403.Synthesis of acid 1404 is completed by either using steps (d)-(f) fromScheme II, or steps (d)-(g) from Scheme III.

Scheme XV, depicted above, can be used to synthesize certain examplecompounds disclosed herein. (Bromomethyl) pyrazole 1501, obtained viasteps (a)-(e) of Scheme II, is converted to phosphonium salt 1502.Treatment with base forms phosphorane ylid 1503; Wittig reaction with anappropriate aldehyde gives alkene 1504. The alkene can be optionallyhydrogenated to give alkane 1506. Synthesis is completed by esterhydrolysis give alkene 1505 or alkane 1507, respectively.

Scheme XVI, depicted above, may be use to prepare certain examplecompounds disclosed herein. Acetonitrile is condensed with an oxalateester to give a ketoester product, which can be isolated as its salt1601. Neutralization of the salt is followed by condensation with asubstituted hydrazine to give a 5-aminopyrazole compound 1602. The aminofunctionality is then substituted by reaction with an organohalide in apalladium (0) mediated reaction, affording 1603, and then protected asits Boc carbamate 1604. Ester reduction, alcohol alkylation, and esterhydrolysis proceeds as before to give acid 1605. The Boc protectinggroup is removed under acidic conditions, affording 1606.

Scheme XVII, depicted above, may be use to prepare certain examplecompounds disclosed herein. 2-Ketosuccinate ester is condensed with asubstituted hydrazine to give 5-hydroxypyrazole compound 1701, shownhere as its keto tautomer. The hydroxy group is alkylated with anelectrophilic arene, such as 2-fluoronitrobenzene, giving ether 1702.The nitro functionality is removed by stepwise reduction with zinc(0) toamine 1703, followed by deamination with alkyl nitrite, yielding 1704.Synthesis of acid 1705 is completed by either using steps (d)-(f) fromScheme II, or steps (d)-(g) from Scheme III.

Scheme XVIII, depicted above, may be use to prepare certain examplecompounds disclosed herein. Nitro acetophenone 1801 is reacted underClaisen conditions with an oxalate ester to give 2,4-diketoester 1802,which is then reacted with a substituted hydrazine in step (c) toconstruct the pyrazole core of 1803, which is alkylated to provide 1804.The ester functionality is reduced to the alcohol (not shown) andalkylated to give ester 1805. At this point, the nitro group is reducedwith zinc to give amine 1806, and acylated using standard couplingreagents to give amide 1807. Synthesis is completed with basichydrolysis of the ester, affording carboxylic acid 1808.

Scheme XIX, depicted above, may be use to prepare certain examplecompounds disclosed herein. In pathway (a), amine 1806, prepared usingthe method of Scheme XVIII, is treated with an organonitrite in thepresence of a disulfide to afford a thioether, which is oxidized tosulfone 1901. In pathway (b), amine 1806 is reacted with a sulfonylchloride to give sulfonamide 1903. In pathway (c), amine 1806 is treatedwith an aldehyde under reductive amination conditions to give amine1905. In pathways (a), (b), and (c), synthesis is completed with basichydrolysis of the ester, affording carboxylic acid 1902, 1904, and 1906,respectively.

Scheme XX, depicted above, may be use to prepare certain examplecompounds disclosed herein. Benzyl ether 206 is prepared by using steps(a)-(e) of Scheme II. Treatment with acid cleaves both the ether groupand the methyl ester to give acid 2001. If desired, synthesis can becontinued by Fischer esterification to 2002, alkylation of the phenolunder basic conditions, and hydrolysis of the methyl ester to give acid2003.

Scheme XXI, depicted above, may be use to prepare certain examplecompounds disclosed herein. Carboxylic acid 207 is prepared by usingsteps (a)-(f) of Scheme II. Treatment of the acid with analkylsulfonamide give ester 2101.

Scheme XXII, depicted above, may be used to prepare certain examplecompounds disclosed herein. Aryllithium 2201, prepared by lithiation,halogen-metal exchange, or other methods that are available in the art,is reacted with N-methyl-N-methoxyacetamide, which affords acetylcompound 2202, which can be transformed to the desired product throughany of the previous schemes.

Scheme XXIII, depicted above, may be used to prepare certain examplecompounds disclosed herein. Carboxylic acid 2301 is converted to thecorresponding alkoxy amide 2302 using standard amide formationprocedures. The alkoxy amide is then reacted with an appropriateorganolithium reagent, which affords ketone compound 2303, which can betransformed to the desired product through any of the previous schemes.

Scheme XXIV, depicted above, may be used to prepare certain examplecompounds disclosed herein. Aryl halide 2401, prepared using any of themethods disclosed herein, is converted to the corresponding arylamine2402. This transformation can be accomplished with a copper-basedcatalyst, or other techniques known in the art. Synthesis can then becompleted using methods disclosed herein.

Scheme XXV, depicted above, may be used to prepare certain examplecompounds disclosed herein. Aryl halide 2501, prepared using any of themethods disclosed herein, is converted to the corresponding arylamide2502. This transformation can be accomplished with a copper-basedcatalyst, or other techniques known in the art. Synthesis can then becompleted using methods disclosed herein.

Scheme XXVI, depicted above, may be used to prepare certain examplecompounds disclosed herein. Aryl halide 2601, prepared using any of themethods disclosed herein, is converted to the corresponding aryl nitrile2602. This transformation can be accomplished with a Pd-based catalyst,or other techniques known in the art. Synthesis can then be completedusing methods disclosed herein.

Scheme XXVII, depicted above, may be used to prepare certain examplecompounds disclosed herein. Carboxylic acid 2701, prepared using any ofthe methods disclosed herein, is converted to the correspondingcarboxylate salt 2702. This transformation can be accomplished with ametal hydroxide or metal oxide. The metal can be chosen from the alkalimetals, alkaline earth metals, or other metals.

Scheme XXVIII, depicted above, may be used to prepare certain examplecompounds disclosed herein. An aryl or heteroaryl halide 2801 isconverted to the corresponding hydrazine 2802. Synthesis of the pyrazolecore is accomplished via condensation with an appropriate carbonylcompound, as disclosed herein. Amine functionality in the aryl orheteroaryl moiety of 2801 can be protected by attachment of a suitableprotecting group, such as the SEM protecting group. The protecting groupcan be removed at a convenient point in synthesis by using methods knownin the art.

Intermediates

The following intermediates were synthesized for use in preparing thecompounds of this disclosure.

Intermediate A-1: 1-(1-Methyl-1H-indol-6-yl)ethan-1-one

6-Bromo-1-methyl-1H-indole

A mixture of 6-bromo-1H-indole (5 g, 25.50 mmol, 1.00 equiv), K₂CO₃ (7g, 50.65 mmol, 2.00 equiv), and CH₃I (7.3 g, 51.43 mmol, 2.00 equiv) inacetone (100 mL) was stirred for 16 h at 55° C., then cooled to rt,diluted with 100 mL H₂O, and extracted with 2×200 mL of EtOAc. Thecombined organic layers were washed with 100 mL of brine, dried overNa₂SO₄, concentrated under vacuum, and purified with silica gelchromatography using EtOAc/petroleum ether (1:10) to afford 3.4 g (63%)of the title compound as a yellow oil. LC-MS: (ES, m/z): 208. ¹H NMR(300 MHz, DMSO-d₆) δ 7.69 (dt, J=1.6, 0.7 Hz, 1H), 7.49 (dd, J=8.4, 0.6Hz, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.13 (dd, J=8.4, 1.8 Hz, 1H), 6.43 (dd,J=3.1, 0.9 Hz, 1H), 3.77 (s, 3H).

1-(1-Methyl-1H-indol-6-yl)ethan-1-one

To a solution of 6-bromo-1-methyl-1H-indole (3.4 g, 16.19 mmol, 1.00equiv) in THF (100 mL) was added BuLi (12 mL, 2.00 equiv, 2.5 M)dropwise with stirring at −78° C. The solution was stirred for 1 h, thenN-methoxy-N-methylacetamide (4.1 g, 39.76 mmol, 2.50 equiv) was addeddropwise with stirring at −78° C. The solution was stirred for 30 min,then warmed to rt and stirred an additional 2 h. The reaction mixturewas cooled to 0° C., then quenched by the addition of 1 M HCl andextracted with 2×200 mL of EtOAc. The combined organic layers werewashed with 100 mL of brine, dried over Na₂SO₄, concentrated undervacuum, and purified with silica gel chromatography usingEtOAc/petroleum ether (1:5) to afford 1.9 g (68%) of the title compoundas a yellow solid. LC-MS: (ES, m/z): 173. ¹H NMR: (300 MHz, DMSO-d₆) δ8.12 (dt, J=1.5, 0.8 Hz, 1H), 7.70-7.59 (m, 2H), 7.57 (d, J=3.0 Hz, 1H),6.51 (dd, J=3.0, 0.9 Hz, 1H), 3.88 (s, 3H), 2.63 (s, 3H).

Intermediate A-2: 1-(1-Methyl-1H-indazol-6-yl)ethan-1-one

1-(1-methyl-1H-indazol-6-yl)ethan-1-one

To a solution of 6-bromo-1-methyl-1H-indazole (2.5 g, 11.85 mmol, 1.00equiv) in THF (50 mL) under N₂ at −78° C. was added n-BuLi (10 mL, 2.00equiv) dropwise with stirring. The solution was stirred for 60 min atthis temperature, then N-methoxy-N-methylacetamide (3 g, 29.09 mmol,2.50 equiv) was added, and the solution was stirred for an additional 60min at this temperature. The resulting solution was stirred for 1 h atrt, cooled to 0° C., quenched by the addition of HCl (1M), and extractedwith 2×100 mL of EtOAc. The combined organic layers were washed with 50mL of brine, dried over Na₂SO₄, concentrated under vacuum, and purifiedwith silica gel chromatography using EtOAc/petroleum ether (1:10) toafford 1.5 g (73%) of the title compound as a yellow oil. LC-MS: (ES,m/z): 174. ¹H NMR: (400 MHz, DMSO-d₆) δ 8.36 (q, J=1.1 Hz, 1H), 8.16 (d,J=1.0 Hz, 1H), 7.86 (dd, J=8.5, 0.8 Hz, 1H), 7.69 (dd, J=8.5, 1.4 Hz,1H), 4.16 (s, 3H), 2.70 (s, 3H).

The following acetyl arenes were obtained from similar routes.

TABLE 1 Synthesis of acetyl arenes from aryl bromides. Aryl bromideProduct Spectral 1-bromo-3-(propan- 1-[3-(Propan-2-yl)phenyl]- A-32-yl)benzene ethan-1-one 6-bromo-1-ethyl-1H- 1-(1-Ethyl-1H-indazol-6-A-4 LC-MS: (ES, indazole yl)ethan-1-one m/z): 189. 1-bromo-3-chloro-5-1-(3-chloro-5-methoxy- A-5 LC-MS: (ES, methoxybenzene phenyl)ethan-1-onem/z): 182. 5-bromo-1-methyl- 1-(1-methyl-1H-indazol-5- A-6 LC-MS: (ES,1H-indazole yl)ethan-1-one m/z): 174. 4-bromo-1-methyl-1-(1-methyl-1H-indazol-4- A-7 LC-MS: (ES, 1H-indazole yl)ethan-1-onem/z): 174. 6-bromo-1-ethyl-1H- 1-(1-ethyl-1H-1,2,3- A-8 LC-MS: (ES,1,2,3-benzotriazole benzotriazol-6-yl)ethan-1- m/z) 189. one

The following acetyl arene intermediates were prepared via Scheme XXII.

Intermediate A-9: 1-(3-Cyclobutoxyphenyl)ethan-1-one

To a mixture of 1-(3-hydroxyphenyl)ethan-1-one (4.5 g, 33.05 mmol, 1.00equiv) and Cs₂CO₃ (10.78 g, 33.09 mmol, 1.00 equiv) in DMA (50 mL) wasadded dropwise bromocyclobutane (9.0 g, 66.67 mmol, 2.00 equiv) withstirring at rt. The resulting mixture was stirred for 16 h at 130° C.,then cooled and diluted with 200 mL of EtOAc. The combined organiclayers were washed with 2×200 mL of H₂O and 2×200 mL of brine, thendried over Na₂SO₄, concentrated under vacuum, and purified with silicagel chromatography using EtOAc/petroleum ether (1:10) to afford 5.0 g(80%) of the title compound as colorless oil. ¹H NMR: (300 MHz, DMSO-d₆)δ 7.53 (ddd, J=7.6, 1.7, 1.1 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.32 (dd,J=2.6, 1.6 Hz, 1H), 7.10 (ddd, J=8.1, 2.7, 1.0 Hz, 1H), 4.83-4.67 (m,1H), 2.55 (s, 3H), 2.47-2.31 (m, 2H), 2.14-1.94 (m, 2H), 1.88-1.72 (m,1H), 1.72-1.56 (m, 1H).

Intermediate A-10: 1-[3-(Oxetan-3-ylmethoxy)phenyl]ethan-1-one

Into a flask under N₂ were combined a solution of oxetan-3-ylmethanol(3.24 g, 36.77 mmol, 1.00 equiv) in THF (100 mL),1-(3-hydroxyphenyl)ethan-1-one (5 g, 36.72 mmol, 1.00 equiv), and PPh3(14.5 g, 1.50 equiv), followed by the addition of DEAD (8.3 g, 47.66mmol, 1.30 equiv) dropwise with stirring at 0° C. The resulting solutionwas stirred for 12 h at rt, then extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, concentrated under vacuum, andpurified by silica gel chromatography with EtOAc/petroleum ether (0-20%)to afford 4.4 g (58%) of the title compound as light yellow oil. LC-MS:(ES, m/z): 206.90. H-NMR: δ_(H) (300 MHz, DMSO-d₆) 7.56 (1H, ddd, J=7.6,1.6, 1.0 Hz), 7.45 (2H, m), 7.23 (1H, ddd, J=8.2, 2.7, 1.1 Hz), 4.71(2H, dd, J=7.9, 6.0 Hz), 4.44 (2H, t, J=6.0, 6.0 Hz), 4.26 (2H, d, J=6.7Hz),3.39 (1H, m), 2.57 (3H, s).

The following alkylated compounds were obtained from Williamsonsynthesis of 3-hydroxyacetophenone.

TABLE 2 Williamson synthesis of alkoxy acetophenones. Base/ Alkyl halidesolvent Temp Product Spectral 3-bromo- Cs₂CO₃/ 130° C. 1-[3-(Oxetan-3-yl- A-11 LC-MS: (ES, oxetane DMA oxy)phenyl]ethan- m/z):193. 1-one Bromocyclo- Cs₂CO₃/ 150° C.  1-(3-cyclopropoxy- A-12 propaneDMA phenyl)ethan-1-one 1-Bromo-2,2- K₂CO₃/ 110° C. 1-[3-(2,2-Dimethylpropoxy)phenyl]- A-13 LC-MS: (ES, dimethyl- DMFethan-1-one m/z): 206.9. propane (Bromo- K₂CO₃/ 110° C. 1-[3-(Cyclobutyl- A-14 LC-MS: (ES, methyl)- DMF methoxy)phenyl]ethan-m/z): 291.25. cyclobutane 1-one (Bromo- K₂CO₃/ 80° C. 1-[3-(Cyclopropyl-A-15 LC-MS: (ES, methyl)- DMF methoxy)phenyl]- m/z): 191. cyclopropaneethan-1-one Iodoethane K₂CO₃/ 90° C. 1-(3-Ethoxy- A-16 LC-MS: (ES, DMFphenyl)ethan-1-one m/z): 165. Benzyl K₂CO₃/ 80° C. 1-[3-(benzyloxy)-A-17 LC-MS: (ES, bromide DMF phenyl]ethan-1-one m/z): 226.95. 1-Bromo-2-K₃PO₄/ 60° C. 1-[3-(2-Methyl- A-18 methylpropane DMSO propoxy)phenyl]-ethan-1-one

Intermediate A-19: 1-(3,5-Dimethoxyphenyl)ethan-1-one

In a flask were combined 1-(3,5-dihydroxyphenyl)ethan-1-one (2 g, 13.15mmol, 1.00 equiv) iodomethane (6.5 g, 45.79 mmol, 4.00 equiv), K₂CO₃(3.6 g, 25.86 mmol, 2.00 equiv) and acetone (40 mL). The resultingmixture was stirred for 16 h at 56° C., then cooled to rt, diluted with100 mL of water, and extracted with 2×50 mL of EtOAc. The combinedorganic layers were washed with 20 mL of brine, dried over Na₂SO₄,concentrated under vacuum, and purified with silica gel chromatographyusing EtOAc/petroleum ether (1:10), to afford 2 g (84%) of the titleproduct as colorless oil. LC-MS: (ES, m/z): 181. ¹H NMR: (300 MHz,DMSO-d₆) δ 7.07 (d, J=2.3 Hz, 2H), 6.77 (t, J=2.3 Hz, 1H), 3.89-3.71 (m,6H), 2.56 (s, 3H).

Intermediate A-20: 1-(3,5-Diethoxyphenyl)ethan-1-one

In a flask were combined 1-(3,5-dihydroxyphenyl)ethan-1-one (5 g, 32.86mmol, 1.00 equiv), iodoethane (20 g, 128.23 mmol, 4.00 equiv), K₂CO₃ (18g, 130.43 mmol, 4.00 equiv), and acetone (100 mL). The resulting mixturewas heated to reflux overnight, then cooled to rt and extracted with3×100 mL of EtOAc. The combined organic layers were dried over Na₂SO₄and concentrated under vacuum to afford 6 g (88%) of the title compoundas a brown solid. LC-MS: (ES, m/z): 208.95.

Intermediate A-21: 1-(3-Ethoxy-5-methoxyphenyl)ethan-1-one

1-(3-Hydroxy-5-methoxyphenyl)ethan-1-one

To a mixture of 1-(3,5-dihydroxy-phenyl)ethan-1-one (5.0 g, 32.86 mmol,1.00 equiv), K₂CO₃ (6.85 g, 49.56 mmol, 1.50 equiv), and acetone (100mL) was added MeI (4.67 g, 32.89 mmol, 1.00 equiv) dropwise withstirring at rt. The resulting solution was heated to reflux for 2 h,concentrated under vacuum, and purified with silica gel chromatographyusing EtOAc/petroleum ether (1:3) to afford 2 g (37%) of the titlecompound as a white solid. LC-MS: (ES, m/z): 167.

1-(3-Ethoxy-5-methoxyphenyl)ethan-1-one

To a mixture of 1-(3-hydroxy-5-methoxyphenyl)ethan-1-one (2 g, 12.04mmol, 1.00 equiv), K₂CO₃ (2.5 g, 18.09 mmol, 1.50 equiv), and DMF (50mL) was added EtI (2.8 g, 17.95 mmol, 1.00 equiv) dropwise with stirringat rt. The resulting solution was stirred for 16 h at 90° C., dilutedwith 100 mL of EtOAc, washed with 1×100 mL of water and 1×100 mL ofbrine, dried over Na₂SO₄, concentrated under vacuum, and purified withsilica gel chromatography using EtOAc/petroleum ether (1:5) to afford950 mg (41%) of the title compound as a colorless oil. LC-MS: (ES, m/z):195. ¹H-NMR: (DMSO, ppm): δ: 7.06 (dq, J=2.9, 1.4 Hz, 2H), 6.75 (t,J=2.3 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 2.56 (s, 3H), 1.34 (t, J=6.9 Hz,3H).

Intermediate A-22: 1-[2-(Propan-2-yloxy)-1,3-oxazol-5-yl]ethan-1-one

2-Hydroxy-1,3-oxazole-5-carboxylic Acid

A solution of ethyl 2-chloro-1,3-oxazole-5-carboxylate (3 g, 17.09 mmol,1.00 equiv) and LiOH (1.7 g, 70.98 mmol, 4.00 equiv) in THF/H₂O (60/15mL) was stirred for 16 h at 30° C. The pH was then adjusted to 4 with 1M HCl, and the resulting solution was extracted with 4×50 mL of EtOAc.The combined organic layers were dried over anhydrous Na₂SO₄ andconcentrated under vacuum to afford 2 g (91%) of the title compound as ayellow solid. LC-MS: (ES, m/z): 129.

2-Hydroxy-N-methoxy-N-methyl-1,3-oxazole-5-carboxamide

A solution of N-methoxy-N-methylamine hydrochloride (1.8 g, 18.45 mmol,1.20 equiv), HATU (7.6 g, 20.54 mmol, 1.30 equiv), DIEA (6 g, 46.43mmol, 3.00 equiv), and 2-hydroxy-1,3-oxazole-5-carboxylic acid (2 g,15.50 mmol, 1.00 equiv) in DMF (60 mL) was stirred for 5 h at roomtemperature. The resulting mixture was concentrated under vacuum andpurified with silica gel chromatography using CH₂Cl₂/MeOH (50:1) toafford 1.3 g (49%) of the title compound as a yellow solid. LC-MS: (ES,m/z): 173.

N-methoxy-N-methyl-2-(propan-2-yloxy)-1,3-oxazole-5-carboxamide Amixture of 2-hydroxy-N-methoxy-N-methyl-1,3-oxazole-5-carboxamide (1.8g, 10.46 mmol, 1.00 equiv), 2-iodopropane (3.6 g, 2.00 equiv), K₂CO₃(2.9 g, 2.00 equiv) and DMF (15 mL) in a 20-mL sealed tube was stirredfor 16 h at 90° C. The reaction mixture was cooled to rt, diluted with20 mL of H₂O, and extracted with 4×20 mL of EtOAc. The combined organiclayers were dried over Na₂SO₄, concentrated under vacuum, and purifiedwith silica gel chromatography using CH₂Cl₂/MeOH (100:1) to afford 1.5 g(67%) of the title compound as a yellow solid. LC-MS: (ES, m/z): 214.

1-[2-(Propan-2-yloxy)-1,3-oxazol-5-yl]ethan-1-one

To a solution ofN-methoxy-N-methyl-2-(propan-2-yloxy)-1,3-oxazole-5-carboxamide (1.5 g,7.00 mmol, 1.00 equiv) in THF (40 mL) under N₂ at −78° C. was added inportions MeMgBr (21 mL, 3.00 equiv). The resulting solution was stirredfor 2 h at rt, cooled to 0° C., quenched by the addition of HCl (1M),and extracted with 2×50 mL of EtOAc. The combined organic layers werewashed with 30 mL of brine, dried over Na₂SO₄, concentrated undervacuum, and purified with silica gel chromatography usingEtOAc/petroleum ether (1:10) to afford 670 mg (57%) of the titlecompound as a yellow solid. LC-MS: (ES, m/z): 169.

Intermediate A-23:1-[1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl]ethan-1-one

N-methoxy-N,1,3-trimethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide

A solution of 1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (2g, 10.19 mmol, 1.00 equiv) methoxy(methyl)amine hydrochloride (1.06 g,10.87 mmol, 1.10 equiv), DIEA (4 g, 30.95 mmol, 3.00 equiv), and HATU(5.8 g, 15.26 mmol, 1.50 equiv) in DMF (30 mL) was stirred for 2 h atrt, diluted with 100 mL of water, and extracted with 2×100 mL of EtOAc.The combined organic layers were washed with 100 mL brine, dried overNa₂SO₄, concentrated under vacuum, and purified with silica gelchromatography using EtOAc/petroleum ether (1:3) to afford 2.2 g (90%)of the title compound as a yellow solid. LC-MS: (ES, m/z): 240.

1-[1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl]ethan-1-one

To a solution of the product from the previous step (2.2 g, 9.19 mmol,1.00 equiv) in THF (50 mL) at −78° C. under N₂ was added methylmagnesiumbromide (1.0 M in THF, 29 mL, 3.00 equiv) dropwise with stirring. Theresulting solution was stirred for 2 h at room temperature, then cooledto 0° C. and then quenched by the addition of aq HCl. The resultingsolution was diluted with 100 mL H₂O and extracted with 2×200 mL ofEtOAc. The combined organic layers were washed with 50 mL of brine,dried over Na₂SO₄, concentrated under vacuum, and purified with silicagel column chromatography using EtOAc/petroleum ether (1:3) to afford1.4 g (78%) of the title compound as a white solid.

LC-MS: (ES, m/z): 195. ¹H NMR (300 MHz, DMSO-d₆) δ 8.04 (s, 1H), 3.86(s, 3H), 2.52 (s, 4H), 2.39 (s, 3H).

Intermediate A-24: 1-(5-Methoxythien-2-yl)ethan-1-one

A mixture of 1-(5-chlorothien-2-yl)-1-ethanone (11 g, 96.35 mmol, 1.00equiv), Cs₂CO₃ (22 g, 1.20 equiv), and Brettphos Pd G3 (550 mg) in MeOH(60 mL) was heated in a sealed tube for 1 hr at 100° C. with microwaveradiation. The resulting mixture was concentrated under vacuum, thenextracted with 3×100 mL of EtOAc. The combined organic layers were driedover anhydrous MgSO₄, concentrated under vacuum, and purified withsilica gel chromatography using EtOAc/petroleum ether (1/50) to afford 5g (33%) of the title product as a yellow solid.

Intermediate A-25: 1-[2-(2-Methylpropoxy)-1,3-thiazol-5-yl]ethan-1-one

To a solution of 1-(2-bromo-1,3-thiazol-5-yl)ethan-1-one (2 g, 9.71mmol, 1.00 equiv) in 2-methylpropan-1-ol (15 mL) in a 40 mL sealed tubeunder N₂ was added sequentially Cs₂CO₃ (6.4 g, 19.64 mmol, 2.00 equiv)and Brettphos Pd G3 (440 mg, 0.49 mmol, 0.05 equiv). The resultingsolution was stirred for 1 h at 90° C. The solution was the cooled,diluted with 50 mL H₂O, and extracted with 2×100 mL of EtOAc. Thecombined organic layers were washed with 50 mL of aq NaCl, dried overanhydrous Na₂SO₄, concentrated under vacuum, and purified with silicagel column using EtOAc/petroleum ether (1:10) to afford 550 mg (28%) ofthe title compound as a yellow oil.

Intermediate A-26: 1-[5-(2-Methylpropoxy)thien-2-yl]ethan-1-one

1-(5-Hydroxythien-2-yl)ethan-1-one

To a solution of 1-(5-Methoxy-thien-2-yl)ethan-1-one was added BBr₃ (180mL) dropwise with stirring at rt. The resulting solution was stirred for2 days at 35° C. The reaction mixture was cooled with a water/ice bath.The reaction was then quenched by the addition of 500 mL of water/ice.The resulting solution was diluted with 500 mL of CH₂Cl₂. The pH valueof the solution was adjusted to 7-8 with (sat) NaHCO₃(aq) (500 mol/L).The mixture was dried over anhydrous Na₂SO₄ and concentrated undervacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:10). This resulted in the title compound as ared oil (5.0 g, 61%).

1-[5-(2-Methylpropoxy)thien-2-yl]ethan-1-one

To a solution of the product from the previous step (800 mg, 5.63 mmol,1.00 equiv) in DMF (20 mL) was added Cs₂CO₃ (3.67 g, 11.26 mmol, 2.00equiv), followed by the addition of 1-iodo-2-methylpropane (2.07 g,11.25 mmol, 2.00 equiv) dropwise with stirring at rt. The resultingsolution was stirred for 16 h at 90° C. The resulting solution wasdiluted with 100 mL of EtOAc then washed with 2×100 mL of water and2×100 mL of brine. The mixture was dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1:10). This resulted in the titlecompound as a yellow oil (600 mg, 54%).

Intermediate A-27: 1-(4-Methoxythien-2-yl)ethan-1-one

To a solution of 1-(4-bromothien-2-yl)ethan-1-one (3.0 g, 14.63 mmol,1.00 equiv) in MeOH (25 mL) was added NaOMe (5.4 mL, 2.00 equiv, 5.4M)at room temperature, followed by CuBr (627 mg, 4.38 mmol, 0.30 equiv) atroom temperature. The resulting solution was stirred for 16 h at 100°C., then diluted with 100 mL of EtOAc, washed with 2×100 mL of brine,dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residuewas purified with silica gel chromatography using EtOAc/petroleum ether(1:20) to afford 700 mg (31%) of the title product as a yellow oil.

Intermediate A-28: 1-[2-(2-Methylpropyl)-1,3-oxazol-5-yl]ethan-1-one

Ethyl 2-(2-methylpropyl)-1,3-oxazole-5-carboxylate

To a solution of ethyl 2-chloro-1,3-oxazole-5-carboxylate (3 g, 17.09mmol, 1.00 equiv) in THF (45 mL), under N₂, was added copper(I) iodide(1.5 g, 7.88 mmol, 0.50 equiv). This was followed by the addition ofbromo(2-methylpropyl)zinc (15 mL, 2.00 equiv) at −5° C. The resultingsolution was stirred for 3 h at room temperature. The reaction was thenquenched by the addition of aq 1 M HCl. The resulting solution wasextracted with 2×100 mL of EtOAc, and the organic layers were combinedand dried over anhydrous Na₂SO₄ and concentrated under vacuum. Theresidue was applied onto a silica gel column with EtOAc/petroleum ether(1:5). This resulted in the title compound as a red oil (1.3 g, 39%).

2-(2-Methylpropyl)-1,3-oxazole-5-carboxylic Acid

To a solution of the product from the previous step (1.3 g, 6.59 mmol,1.00 equiv) in THF/H₂O (20/5 mL) was added LiOH (600 mg, 25.05 mmol,4.00 equiv). The resulting solution was stirred for 3 h at roomtemperature. The reaction mixture was cooled with a water/ice bath. ThepH value of the solution was adjusted to 1 with aq 1 M HCl. Theresulting solution was extracted with 2×50 mL of EtOAc, and the organiclayers were combined and dried over anhydrous Na₂SO₄ and concentratedunder vacuum. This resulted in the title compound as a red solid (1 g,90%).

1-[2-(2-Methylpropyl)-1,3-oxazol-5-yl]ethan-1-one

To a solution of the product from the previous step (1 g, 5.91 mmol,1.00 equiv) in Et₂O (30 mL), under N₂, was added MeLi (7.4 mL, 2.00equiv). The resulting solution was stirred for 3 h at 0° C. in awater/ice bath. The reaction was then quenched by the addition of aq HCl(1M). The resulting solution was extracted with 2×50 mL of EtOAc, andthe organic layers were combined and dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with EtOAc/petroleum ether (1:5). This resulted in the titlecompound as a red oil (800 mg, 81%).

Intermediate A-29: 1-(1-methyl-1H-1,3-benzodiazol-6-yl)ethan-1-one

N-methoxy-N,1-dimethyl-1H-1,3-benzodiazole-6-carboxamide

To a solution of 1-methyl-1H-1,3-benzodiazole-6-carboxylic acid (5.0 g,28.38 mmol, 1.00 equiv) in CH₂Cl₂ (100 mL) was addedmethoxy(methyl)amine hydrochloride (2.78 g, 28.50 mmol, 1.00 equiv), EDC(6.54 g, 42.13 mmol, 1.20 equiv), followed by the addition of DMAP (3.46g, 28.32 mmol, 1.00 equiv), in portions at rt. The resulting solutionwas stirred for 16 h, concentrated under vacuum, and purified withsilica gel chromatography using CH₂Cl₂/MeOH (100:1) to afford 4.0 g(64%) of the title compound as a yellow solid. LC-MS: (ES, m/z):[M+1]=220.

1-(1-methyl-1H-1,3-benzodiazol-6-yl)ethan-1-one

To a solution of the product from the previous step (2.0 g, 9.12 mmol,1.00 equiv) in THF (60 mL) under N₂ was added MeMgBr (9.1 mL, 3.00equiv) dropwise with stirring at −60° C. The resulting mixture wasstirred at this temperature for 30 min, allowed to warm to rt, thenstirred for 2 h at rt. The reaction was then quenched by the addition ofwater/ice. The resulting solution was extracted with 100 mL of EtOAc,dried over Na₂SO₄, concentrated under vacuum, and purified with silicagel chromatography using with CH₂Cl₂/MeOH (50:1) to afford 1.3 g (82%)of the title compound as a yellow solid.

Intermediate A-30: 3-Acetyl-N-(propan-2-yl)benzamide

To a suspension of 3-acetylbenzoic acid (10 g, 60.92 mmol), HATU (20 g,52.60 mmol,) and propan-2-amine (4 g, 67.67 mmol) in DMF (180 mL) at −5°C. was added dropwise DIEA. The resulting mixture was stirred at roomtemperature for 2 h under N₂, then poured into 100 mL H₂O, and extractedwith EtOAc (3×100 mL). The combined organic layers were washed with 300mL brine, dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. This resulted in 11 g (88%) of the title product as a yellowsolid.

The following 2,4-dioxobutanoate esters were synthesized for use inpreparing the compounds of this disclosure, including, but not limitedto, use in Scheme I.

Intermediate B-1: Methyl 4-(2-methoxyphenyl)-2,4-dioxobutanoate

To a solution of 1-(2-methoxyphenyl)ethan-1-one (1 g, 6.66 mmol, 1.00equiv) in MeOH (20 mL) was added sequentially dimethyl oxalate (2.36 g,19.99 mmol, 3.00 equiv), then MeONa (3.7 mL, 3.00 equiv, 5.4 M). Theresulting solution was stirred overnight at 30° C. then quenched by theaddition of water/ice. The pH value of the solution was adjusted to 5with aq 1 M HCl. The resulting solution was extracted with 3×50 mL ofEtOAc, and the organic layers were combined and dried over anhydrousNa₂SO₄ and concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/hexane (1/4). This resulted in the titlecompound as a yellow solid (1.2 g, 76%).

Intermediate B-2: Methyl 4-(3-methoxyphenyl)-2,4-dioxobutanoate

To a solution of 1-(3-methoxyphenyl)ethan-1-one (10 g, 66.59 mmol, 1.00equiv) in MeOH (200 mL) was added sequentially NaOMe (30 mL), anddimethyl oxalate (10.2 g, 86.38 mmol, 1.3 equiv). The resulting solutionwas stirred for 8 h at room temperature. The reaction mixture was cooledto 0° C. with a water/ice bath. The resulting solution was diluted with200 mL of EtOAc. The pH value of the solution was adjusted to 3 with aqHCl (3 mol/L). The resulting solution was extracted with 2×300 mL ofEtOAc, and the organic layers were combined and dried over anhydrousNa₂SO₄ and concentrated under vacuum. This resulted in the titlecompound as a yellow solid (11 g, 70%).

Intermediate B-3: Methyl4-[3-(oxetan-3-ylmethoxy)phenyl]-2,4-dioxobutanoate

In a 100-mL flask were combined a solution of1-[3-(oxetan-3-ylmethoxy)-phenyl]ethan-1-one (Int. A-10, 3 g, 14.55mmol, 1.00 equiv) in MeOH (40 mL), dimethyl oxalate (3.42 g, 28.96 mmol,2.00 equiv), and a solution of MeONa (2.36 g, 43.70 mmol, 3.00 equiv) inMeOH (8 mL). The resulting solution was stirred for 12 h at rt, thenpoured onto ice/water. The pH was adjusted to 3 with HCl. The solidsthat formed were collected by filtration, affording 3.2 g (75%) of thetitle compound as a light yellow solid. LC-MS:(ES, m/z): 293.0. ¹H-NMR:6H (300 MHz, DMSO-d₆) 7.68 (1H, d, J=7.7 Hz), 7.53 (2H, m), 7.30 (1H,m), 7.14 (1H, s), 4.72 (2H, dd, J=7.9, 6.0 Hz), 4.45 (2H, t, J 6.0, 6.0Hz), 4.30 (2H, d, J=6.7 Hz), 3.86 (3H, s), 3.40 (1H, tt, J=8.0, 8.0,6.3, 6.3 Hz).

The following substituted 4-aryl-2,4-dioxobutanoate esters were obtainedfrom Claisen condensation of an 1-arylethanone with an oxalic ester.

TABLE 3 Claisen synthesis of 4-aryl-2,4-dioxobutanoate esters. R_(B)OH/time/ Product temp Aryl ethanone 4-aryl-2,4-dioxobutanoate esterSpectral MeOH/ 1-(3-nitrophenyl)- Methyl 4-(3-nitrophenyl)-2,4- B-4 12hr/rt ethan-1-one dioxobutanoate MeOH/ 1-(Pyridin-2- Methyl2,4-dioxo-4-(pyridin- B-5 LC-MS: 12 hr/rt yl)ethan-1-one 2-yl)butanoate(ES, m/z): 291.25. MeOH/ 1-(2,3-Dihydro- Methyl 4-(2,3-dihydro-1,4- B-6LC-MS: 12 hr/ 1,4-benzodioxin- benzodioxin-6-yl)-2,4- (ES, m/z): 30° C.6-yl)ethan-1-one dioxobutanoate 265. MeOH/ 1-(2H-1,3-Benzo- Methyl4-(2H-1,3- B-7 LC-MS: 16 hr/rt dioxol-5-yl)ethan- benzodioxol-5-yl)-2,4-(ES, m/z): 1-one dioxobutanoate 251. MeOH/ 1-(1-Methyl-1H- Methyl4-(1-methyl-1H- B-8 LC-MS: 16 hr/ pyrazol-4-yl)-pyrazol-4-yl)-2,4-dioxo- (ES, m/z): 40° C. ethan-1-one butanoate 211EtOH/5 hr/ 1-(1-Benzothio- Ethyl 4-(1-benzothiophen-2- B-9 LC-MS: rtphen-2-yl)ethan- yl)-2,4-dioxobutanoate (ES, m/z): 1-one 277 MeOH/1-(4-Bromothien- Methyl 4-(4-bromothien-2- B-10 2 hr/ 2-yl)ethanoneyl)-2,4-dioxobutanoate 60° C. EtOH/ A-1 Ethyl 4-(1-methyl-1H-indol- B-11LC-MS: 16 hr/rt 6-yl)-2,4-dioxobutanoate (ES, m/z): 273. EtOH/ A-2 Ethyl4-(1-methyl-1H- B-12 LC-MS: 16 hr/rt indazol-6-yl)-2,4- (ES, m/z):dioxobutanoate 274. MeOH/ A-3 Methyl 4-[3-(propan-2-yl)- B-13 16 hr/rtphenyl]2,4-dioxobutanoate MeOH/ A-4 Methyl 4-(1-ethyl-1H- B-14 LC-MS: 16hr/rt indazol-6-yl)-2,4- (ES, m/z): dioxobutanoate 275. EtOH/ A-4 Ethyl4-(1-ethyl-1H-indazol- B-15 LC-MS: 16 hr/rt 6-yl)-2,4-dioxobutanoate(ES, m/z): 288. MeOH/ A-5 Methyl 4-(3-chloro-5- B-16 LC-MS: 16 hr/rtmethoxyphenyl)-2,4- (ES, m/z): dioxobutanoate 271 EtOH/ A-6 Ethyl4-(1-methyl-1H- B-17 LC-MS: 16 hr/rt indazol-5-yl)-2,4- (ES, m/z):dioxobutanoate 274. EtOH/ A-7 Ethyl 4-(1-methyl-1H- B-18 LC-MS: 16 hr/rtindazol-4-yl)-2,4- (ES, m/z): dioxobutanoate 274. MeOH/ A-8 Methyl4-(1-ethyl-1H-1,2,3- B-19 LC-MS: 16 h/rt benzotriazol-6-yl)-2,4- (ES,m/z): dioxobutanoate 275 EtOH/ A-9 Ethyl 4-(3-cyclo- B-20 LC-MS: 16hr/rt butoxyphenyl)-2,4- (ES, m/z): dioxobutanoate 291. EtOH/ A-11 Ethyl4-[3-(oxetan-3-yloxy)- B-21 LC-MS: 12 hr/rt phenyl]-2,4-dioxobutanoate(ES, m/z): 293. MeOH/ A-12 Methyl 4-(3-cyclopropoxy- B-22 LC-MS: 12hr/rt phenyl)-2,4-dioxobutanoate (ES, m/z): 262.85. MeOH/ A-13 Methyl4-[3-(2,2-dimethyl- B-23 LC-MS: 12 hr/rt propoxy)phenyl]-2,4-dioxo- (ES,m/z): butanoate 292.95. MeOH/ A-14 Methyl 4-[3-(cyclobutyl- B-24 LC-MS:12 hr/rt methoxy)phenyl]-2,4-dioxo- (ES, m/z): butanoate 290.95. MeOH/A-15 Methyl 4-[3-(cyclopropyl- B-25 LC-MS: 16 hr/rtmethoxy)phenyl]-2,4-dioxo- (ES, m/z): butanoate 276. EtOH/ A-16 Ethyl4-(3-ethoxyphenyl)-2,4- B-26 LC-MS: 16 hr/rt dioxobutanoate (ES, m/z):264. MeOH/ A-17 Methyl 4-[3-(benzyloxy)- B-27 LC-MS: 12 hr/rtphenyl]-2,4-dioxobutanoate (ES, m/z): 313.1. MeOH/ A-18 Methyl4-[3-(2-methyl- B-28 LC-MS: 16 hr/rt propoxy)phenyl]-2,4- (ES, m/z):dioxobutanoate 279. MeOH/ A-19 Methyl 4-(3,5- B-29 LC-MS: 16 hr/rtdimethoxyphenyl)-2,4- (ES, m/z): dioxobutanoate 267. MeOH/ A-20 Methyl4-(3,5-diethoxy- B-30 LC-MS: 12 hr/rt phenyl)-2,4-dioxobutanoate (ES,m/z): 295.2. MeOH/ A-21 Methyl 4-(3-ethoxy-5- B-31 LC-MS: 16 hr/rtmethoxyphenyl)-2,4- (ES, m/z): dioxobutanoate 281 EtOH/5 hr/ A-22 Ethyl2,4-dioxo-4-[2-(propan- B-32 LC-MS: rt 2-yloxy)-1,3-oxazol-5-yl]- (ES,m/z): butanoate 270 MeOH/ A-23 Methyl 4-[1,3-dimethyl-1H- B-33 LC-MS: 16h/rt thieno[2,3-c]pyrazol-5-yl]- (ES, m/z): 2,4-dioxobutanoate 281 MeOH/A-24 Methyl 4-(5-2-methoxythien- B-34 16 h/rt 2-yl)-2,4-dioxobutanoateMeOH/ A-26 Methyl 4-(5-(2- B-35 16 h/rt methylpropoxy)thien-2-yl)-2,4-dioxobutanoate EtOH/5 h/ A-28 4-[2-(2-Methylpropyl)-1,3- B-36 rtoxazol-5-yl]-2,4- dioxobutanoate MeOH/ A-29 Methyl 4-(1-methyl-1H-1,3-B-37 LC-MS: 16 h/rt benzodiazol-6-yl)-2,4- (ES, m/z): dioxobutanoate[M + 1] = 261 MeOH/ A-30 Methyl 4-[3-[(propan-2-yl)- B-38 16 h/rtcarbamoyl]phenyl]-2,4- butanedioate

Intermediate B-39: Ethyl4-[2-(2-methylpropoxy)-1,3-thiazol-5-yl]-2,4-dioxobutanoate

To a solution of Int. A-25 (500 mg, 2.51 mmol, 1.00 equiv) in THF (10mL) was added sequentially diethyl oxalate (1100 mg, 7.53 mmol, 2.00equiv), and t-BuOK (850 mg, 7.58 mmol, 3.00 equiv). The resultingsolution was stirred for 4 h at room temperature followed by dilutionwith 20 mL of H₂O, extraction with 2×30 mL of EtOAc and the organiclayers were combined and dried over anhydrous Na₂SO₄ and concentratedunder vacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:4). This resulted in the title compound as ayellow solid (400 mg, 53%)

Intermediate B-40: Ethyl 2,4-dioxo-5-phenylpentanoate

To a solution of 1-phenyl-2-propanone (1 g, 8.32 mmol, 1.00 equiv) inTHF (25 mL) was added NaH (269 mg, 11.21 mmol, 1.50 equiv), in portionsat 0° C. in 30 min, followed by the addition of diethyl oxalate (1.64 g,11.22 mmol, 1.50 equiv). The resulting solution was stirred for 1 h atroom temperature, then cooled to 0° C. The reaction was then quenched bythe addition of 20 mL of water. The resulting solution was extractedwith 3×50 mL of EtOAc, and the combined organic layers were dried overanhydrous Na₂SO₄, concentrated under vacuum, and purified with silicagel chromatography using EtOAc/petroleum ether (1:40) to afford 700 mg(36%) of the title product as a yellow liquid.

The following substituted ketoesters were also used in the synthesis ofpyrazoles.

Intermediate B-41: Methyl2,4-dioxo-4-(1-propyl-1H-indazol-6-yl)butanoate Intermediate B-42:Methyl 4-(3-cyclobutoxyphenyl)-2,4-dioxobutanoate

The following arylhydrazine intermediates were synthesized for use inpreparing the compounds of this disclosure, including, but not limitedto, use in Scheme I.

Intermediate C-1: 2-(Difluoromethoxy)phenyl]hydrazine trifluoroacetate

Boc-protected 2-(difluoromethoxy)phenyl]hydrazine

To a solution of 1-bromo-2-(difluoromethoxy)benzene (8.0 g, 35.87 mmol,1.00 equiv), (tert-butoxy)-carbohydrazide (5.68 g, 42.98 mmol, 1.20equiv), and BrettPhos Pd G3 (1.74 g, 1.92 mmol, 0.05 equiv) in dioxane(60 mL) under N₂ was added Cs₂CO₃ (11.70 g, 35.91 mmol, 1.00 equiv), inportions at room temperature. The resulting solution was stirred for 16h at 100° C., then cooled, diluted with 200 mL of EtOAc, washed with 200mL of brine, dried over Na₂SO₄ and concentrated under vacuum. The crudeproduct was purified with silica gel chromatography usingEtOAc/petroleum ether (1:5) to afford 8.0 g (81%) of the title compoundas an orange solid. LC-MS: (ES, m/z): 275. ¹H NMR (400 MHz, DMSO-d₆) δ8.83 (s, 1H), 7.29-7.22 (m, 1H), 7.07 (q, J=7.7 Hz, 2H), 6.80-6.68 (m,2H), 1.42 (s, 9H).

2-(Difluoromethoxy)phenyl]hydrazine trifluoroacetate

A solution of the product from the previous step (2.0 g, 7.29 mmol, 1.00equiv) and TFA (10 mL) in CH₂Cl₂ (20 mL) was stirred for 2 h at roomtemperature, then concentrated under vacuum, to afford 1.0 g (48%) ofthe title compound as a brown oil. LC-MS: (ES, m/z): 175.

The following arylhydrazines were synthesized from the correspondingaryl halides using similar procedures.

TABLE 4 Synthesis of aryl hydrazines from aryl bromides. The compoundswere isolated as trifluoroacetate salts. Aryl bromide Product Spectral1-Bromo-2-ethoxy- (2- C-2 LC-MS: benzene Ethoxyphenyl)hydrazine (ES,m/z): 152. 7-Bromo-1-methyl- 7-Hydrazinyl-1-methyl- C-3 LC-MS:1H-indazole 1H-indazole (ES, m/z): 163. 4-Bromo-1-methyl-4-Hydrazinyl-1-methyl- C-4 LC-MS: 1H-indazole 1H-indazole (ES, m/z):162. 7-Bromo-1-ethyl- 1-Ethyl-7-hydrazinyl-1H- C-5 LC-MS: 1H-indazoleindazole (ES, m/z): 277. 1-Bromo-2-(propan- [2-(Propan-2-yloxy)- C-6LC-MS: 2-yloxy)benzene phenyl]hydrazine (ES, m/z): 274.

The free amino groups of the following reactants were first protectedwith SEM groups (NaH; SEM-Cl). Treatment of the coupling product withTFA for removal of the Boc groups also accomplished removal of the SEMprotecting groups.

TABLE 5 Synthesis of aryl hydrazines from aryl bromides. Aryl bromideProduct Spectral 4-Bromo-1H- 4-Hydrazinyl-1H-indazole C-7 LC-MS:indazole (ES, m/z): 148.9. 7-Bromo-1H- 7-Hydrazinyl-1H-indazole C-8LC-MS: indazole (ES, m/z): 379. 4-Bromo-3-methyl-4-Hydrazinyl-3-methyl-1H- C-9 LC-MS: 1H-indazole indazole (ES, m/z):163.2. 7-Bromo-1-methyl- 7-Hydrazinyl-1-methyl-1H-1,3- C-10 1H-1,3-benzodiazole trifluoroacetate benzodiazole 7-Bromo-1,3-7-Hydrazinyl-1,3-dimethyl-1H- C-11 LC-MS: dimethyl-1H- indazole (ES,m/z): indazole 177.1.

Intermediate C-12: 7-Hydrazinyl-1-methyl-1H-1,2,3-benzotriazoletrifluoroacetate

2-Bromo-N-methyl-6-nitroaniline A mixture of1-bromo-2-fluoro-3-nitro-benzene (7 g, 31.82 mmol, 1.00 equiv), K₂CO₃(8.8 g, 63.21 mmol, 2.00 equiv), and CH₃NH₂ (10 mL, 33%) in CH₂Cl₂ (50mL) was stirred 16 h at rt, then diluted with 100 mL of water. Theresulting solution was extracted with 2×200 mL of CH₂C₁₂. The combinedorganic layers were washed with 50 mL of brine, dried over Na₂SO₄, andconcentrated under vacuum to afford 7 g (95%) of the title compound as ared oil. LC-MS: (ES, m/z): 230. ¹H NMR (400 MHz, DMSO-d₆) δ 7.77 (ddd,J=9.8, 8.0, 1.6 Hz, 2H), 6.70 (t, J=8.0 Hz, 1H), 6.43-6.19 (m, 1H), 2.71(d, J=5.3 Hz, 3H).

6-Bromo-1-N-methylbenzene-1,2-diamine

A mixture of the product from the previous step (8 g, 34.62 mmol, 1.00equiv) and Zn (4 g, 62.50 mmol, 2.00 equiv) in AcOH (120 mL) was stirredfor 16 h at rt. The solids were removed by filtration, and the filtratewas concentrated under vacuum. The residue was dissolved in 300 mL ofCH₂Cl₂, washed with 100 mL of NaHCO₃, dried over Na₂SO₄, andconcentrated under vacuum, to afford 4 g (57%) of the title compound asa black oil. LC-MS: (ES, m/z): 201.

7-Bromo-1-methyl-1H-1,2,3-benzotriazole

To a solution of the product from the previous step (4 g, 19.89 mmol,1.00 equiv) in HBr/H₂O (60 mL) at 5° C. was added a solution of NaNO₂(2.07 g, 1.50 equiv) in H₂O (10 mL) dropwise with stirring. The solutionwas stirred for 4 h at 15-20° C. The pH was adjusted to 8 with NaHCO₃(3mol/L). The resulting solution was extracted with 2×200 mL of EtOAc. Thecombined organic layers were washed with 100 mL of brine, dried overanhydrous Na₂SO₄, concentrated under vacuum, and purified with silicagel chromatography using EtOAc/petroleum ether (1:5), to afford 4 g(95%) of the title compound as a black solid. LC-MS: (ES, m/z): 212. ¹HNMR (400 MHz, DMSO-d₆) δ 8.06 (dd, J=8.3, 0.8 Hz, 1H), 7.84-7.73 (m,1H), 7.31 (dd, J=8.4, 7.5 Hz, 1H), 4.51 (s, 3H).

7-Hydrazinyl-1-methyl-1H-1,2,3-benzotriazole trifluoroacetate wasprepared from the previous compound by using the procedure of C-1.LC-MS: (ES, m/z): 163.

Intermediate C-13: [(2-Chlorophenyl)methyl]hydrazine dihydrochloride

To a solution of hydrazine hydrate (85%) (31 g, 8.50 equiv) in EtOH (100mL) was added dropwise a solution of 1-chloro-2-(chloromethyl)benzene(10 g, 62.10 mmol, 1.00 equiv) in EtOH (50 mL) over 1 hr at 70° C. Theresulting solution was stirred for 1 h at 70° C., concentrated undervacuum diluted with water, and extracted with EtOAc three times. Thecombined organic layers were chilled to 0° C., then a solution of 4N HClin dioxane was added. The solids that formed were collected byfiltration, affording 6.1 g (63%) of the title product as a white solid.

Intermediate D-1: Ethyl5-[[(tert-butoxy)carbonyl](phenyl)amino]-1-[(2-chlorophenyl)methyl]-1H-pyrazole-3-carboxylate

Ethyl 3-cyano-2-(potassiooxy)prop-2-enoate

To a solution of diethyl oxalate (5.06 g, 34.62 mmol, 1.00 equiv) inCH3CN (20 mL) was added t-BuOK (3.90 g, 34.76 mmol, 1.12 equiv), inportions at rt. The resulting solution was stirred for 1.5 h at rt. Thesolids that formed were collected by filtration. This resulted in 5.09 g(82%) of the title product as a yellow solid.

Ethyl 5-amino-1-[(2-chlorophenyl)methyl]-1H-pyrazole-3-carboxylate

To a solution of the product from the previous step (2.0 g, 11.16 mmol,1.00 equiv) in 1,4-dioxane (20 mL) was added TFA (2 mL) dropwise withstirring at rt. The resulting mixture was stirred at rt for 30 min. Tothis was added Int. C-13 (2.0 g, 12.77 mmol, 1.15 equiv), in portions atrt. The resulting solution was stirred overnight at rt, then dilutedwith 200 mL of EtOAc, washed with 2×200 mL of brine, dried overanhydrous Na₂SO₄, concentrated under vacuum, and purified with silicagel chromatography using EtOAc/petroleum ether (1:3) to afford 1.8 g(58%) of the title compound as a yellow oil.

Ethyl1-[(2-chlorophenyl)methyl]-5-(phenylamino)-1H-pyrazole-3-carboxylate

A solution of the product from the previous step (1.0 g, 3.57 mmol, 1.00equiv), iodobenzene (768 mg, 3.76 mmol, 1.05 equiv), Brettphos Pd G3precatalyst (326 mg, 0.36 mmol, 0.10 equiv), and Cs₂CO₃ (1.4 g, 4.30mmol, 1.20 equiv) in 1,4-dioxane (20 mL). The resulting solution wasstirred in a sealed tube under N₂ at 90° C. for 3 h. The resultingsolution was diluted with 200 mL of EtOAc, washed with 2×200 mL ofbrine, dried over Na₂SO₄, concentrated under vacuum, and purified withsilica gel chromatography using petroleum ether:EtOAc:DCM (3:1:0.1) toafford 1.3 g (102%) of the title product as a yellow solid.

Ethyl5-[[(tert-butoxy)carbonyl](phenyl)amino]-1-[(2-chlorophenyl)methyl]-1H-pyrazole-3-carboxylate

To a solution of the product from the previous step (800 mg, 2.25 mmol,1.00 equiv) and DMAP (548 mg, 4.49 mmol, 2.00 equiv) in toluene (20 mL)was added di-tert-butyl dicarbonate (980 mg, 4.49 mmol, 2.00 equiv), inportions at rt. The resulting solution was heated at reflux overnight.The resulting solution was diluted with 200 mL of EtOAc, washed with2×100 mL of brine, dried over anhydrous Na₂SO₄, concentrated undervacuum, and purified with silica gel chromatography usingEtOAc/petroleum ether (1:3) to afford 1.0 g (101%) of the title productas a colorless oil.

Intermediate D-2: Methyl5-(3-cyclopropoxyphenyl)-1H-pyrazole-3-carboxylate

A solution of Int. B-22 (2 g, 7.63 mmol, 1.00 equiv) and hydrazinehydrate (540 mg, 10.00 mmol, 1.30 equiv) in AcOH (20 mL) was stirred for2 h at 100° C., then cooled. The pH was adjusted to 7 with satd NaHCO₃,and the resulting solution was extracted with 3×100 mL EtOAc. Thecombined organic layers were dried over Na₂SO₄, concentrated undervacuum, and purified with silica gel chromatography using EtOAc/hexane(1/1) to affird 1.5 g (76%) of the title compound as a light yellowsolid. LC-MS: (ES, m/z): 259. ¹H NMR (300 MHz, MeOD) δ 7.35 (m, 3H),7.13 (d, J=21.3 Hz, 2H), 3.92 (s, 3H), 3.84 (dp, J=6.4, 3.0, 3.0, 2.9,2.9 Hz, 1H), 0.82 (m, 2H), 0.72 (m, 2H).

The following substituted 3-pyrazolecarboxylic esters were obtained fromcondensation of methyl 4-(aryl)-2,4-dioxobutanoate with hydrazine:

TABLE 6 Pyrazole synthesis with hydrazine. Diketone Product Spectral B-2Methyl 5-(3-methoxyphenyl)-1H-pyrazole-3- D-3 carboxylate B-4 Methyl5-(3-nitrophenyl)-1H-pyrazole-3- D-4 carboxylate B-6 Methyl5-(2,3-dihydro-1,4-benzodioxin-6-yl)- D-5 LC-MS: (ES,1H-pyrazole-3-carboxylate m/z): 261. B-7 Methyl5-(2H-1,3-benzodioxol-5-yl)-1H-pyrazole- D-6 LC-MS: (ES, 3-carboxylatem/z): 247. B-8 Methyl 5-(1-methyl-1H-pyrazol-4-yl)-1H- D-7 LC-MS: (ES,pyrazole-3-carboxylate m/z): 207. B-9 Ethyl5-(1-benzothiophen-2-yl)-1H-pyrazole-3- D-8 LC-MS: (ES, carboxylatem/z): 272. B-11 Ethyl 5-(1-methyl-1H-indol-6-yl)-1H-pyrazole- D-9 LC-MS:(ES, 3-carboxylate m/z): 269. B-12 Ethyl5-(1-methyl-1H-indazol-6-yl)-1H- D-10 LC-MS: (ES, pyrazole-3-carboxylatem/z): 271. B-14 Methyl 5-(1-ethyl-1H-indazol-6-yl)-1H- D-11 LC-MS: (ES,pyrazole-3-carboxylate m/z): 271. B-16 Methyl5-(3-chloro-5-methoxyphenyl)-1H- D-12 LC-MS: (ES, pyrazole-3-carboxylatem/z): 252. B-17 Ethyl 5-(1-methyl-1H-indazol-5-yl)-1H- D-13 LC-MS: (ES,pyrazole-3-carboxylate m/z): 270. B-18 Ethyl5-(1-methyl-1H-indazol-4-yl)-1H- D-14 LC-MS: (ES, pyrazole-3-carboxylatem/z): 270. B-19 Methyl 5-(1-ethyl-1H-1,2,3-benzotriazol-6-yl)- D-15LC-MS: (ES, 1H-pyrazole-3-carboxylate m/z): 271. B-20 Ethyl5-(3-cyclobutoxyphenyl)-1H-pyrazole-3- D-16 LC-MS: (ES, carboxylatem/z): 286. B-23 Methyl 5-[3-(2,2-dimethylpropoxy)phenyl]-1H- D-17 LC-MS:(ES, pyrazole-3-carboxylate m/z): 289.1. B-26 Ethyl5-(3-ethoxyphenyl)-1H-pyrazole-3- D-18 LC-MS: (ES, carboxylate m/z):260. B-27 Methyl 5-[3-(benzyloxy)phenyl]-1H-pyrazole- D-19 LC-MS: (ES,3-carboxylate m/z): 309.1. B-28 Methyl 5-[3-(2-methylpropoxy)phenyl]-1H-D-20 pyrazole-3-carboxylate B-29 Methyl5-(3,5-dimethoxyphenyl)-1H-pyrazole- D-21 LC-MS: (ES, 3-carboxylatem/z): 263. B-30 Methyl 5-(3,5-diethoxyphenyl)-1H-pyrazole-3- D-22 LC-MS:(ES, carboxylate m/z): 290.95. B-31 Methyl5-(3-ethoxy-5-methoxyphenyl)-1H- D-23 LC-MS: (ES, pyrazole-3-carboxylatem/z): 277. B-32 Ethyl 5-[2-(propan-2-yloxy)-1,3-oxazol-5-yl]- D-24LC-MS: (ES, 1H-pyrazole-3-carboxylate m/z): 266. B-33 Methyl5-[1,3-dimethyl-1H-thieno[2,3- D-25 LC-MS: (ES,c]pyrazol-5-yl]-1H-pyrazole-3-carboxylate m/z): 277. B-38 Methyl5-[3-[(propan-2-yl)carbamoyl]phenyl]- D-26 1H-pyrazol-3-carboxylate

Intermediate D-27: Methyl1-[(2-chlorophenyl)methyl]-5-(3-(propan-2-yl)phenyl)-1H-pyrazole-3-carboxylate

A solution of Int. B-13 (1.0 g, 4.03 mmol, 1.00 equiv) and Int. C-13(1.38 g, 6.01 mmol, 1.50 equiv) in AcOH (20 mL) was stirred for 2 h at100° C., then concentrated under vacuum, diluted with 200 mL of EtOAc,washed with 2×100 mL of sat NaHCO₃, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The crude product was purified with silicagel chromatography using EtOAc/petroleum ether (1:5) to afford 1.05 g(71%) of the title product as a yellow solid.

Intermediate D-28: Methyl1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

To a solution of Int. B-2 (3.8 g, 16.09 mmol, 1.00 equiv) in MeOH (80mL) was added Int. C-13 (4.8 g, 20.91 mmol, 1.30 equiv). The resultingsolution was stirred for 3 h at 65° C., then concentrated under vacuum,and purified with silica gel chromatography using EtOAc/petroleum ether(1:2), to afford the title compound as a white solid (5.5 g, 96%).

The following substituted 3-pyrazolecarboxylic esters were obtained fromcondensation of methyl 4-(aryl)-2,4-dioxobutanoate with varioussubstituted hydrazines:

TABLE 7 Pyrazole synthesis with substituted hydrazines. Ar₁NHNH₂Diketone Product Spectral Phenylhydrazine B-28 Methyl5-[3-(2-methylpropoxy)- D-29 LC-MS: (ES, phenyl]-1-phenyl-1H-pyrazole-3-m/z): 357. carboxylate (2-Bromo- B-14 Methyl 1-(2-bromophenyl)-5-(1-D-30 LC-MS: (ES, phenyl)hydrazine ethyl-1H-indazol-6-yl)-1H- m/z):425.1. pyrazole-3-carboxylate (2-Bromo- B-18 Ethyl1-(2-bromophenyl)-5-(1- D-31 LC-MS: (ES, phenyl)hydrazinemethyl-1H-indazol-6-yl)-1H- m/z): 425. pyrazole-3-carboxylate (2-Bromo-B-23 Methyl 1-(2-bromophenyl)-5-[3- D-32 LC-MS: (ES, phenyl)hydrazine(2,2-dimethylpropoxy)phenyl]-1H- m/z): 443.1. pyrazole-3-carboxylate(2-Bromo- B-29 Methyl 1-(2-bromophenyl)-5-(3,5- D-33 LC-MS: (ES,phenyl)hydrazine dimthoxyphenyl)-1H-pyrazole-3- m/z): 417. carboxylate(2-Bromo- B-41 Methyl 1-(2-bromophenyl)-5-(1- D-34 LC-MS: (ES,phenyl)hydrazine propyl-1H-indazol-6-yl)-1H- m/z): 439.1.pyrazole-3-carboxylate (2-Bromo- B-42 Methyl 1-(2-bromophenyl)-5-(3-D-35 LC-MS: (ES, phenyl)hydrazine cyclobutoxyphenyl)-1H-pyrazole- m/z):441.2. 3-carboxylate (2-Fluorophenyl)- B-3 Methyl1-(2-fluorophenyl)-5-[3- D-36 LC-MS: (ES, hydrazine(oxetan-3-ylmethoxy)phenyl]-1H- m/z): 383.1. pyrazole-3-carboxylate(2-Fluorophenyl)- B-20 Ethyl 5-(3-cyclobutoxyphenyl)-1- D-37 LC-MS: (ES,hydrazine (2-fluorophenyl)-1H-pyrazole-3- m/z): 381. carboxylate(2-Fluorophenyl)- B-21 Ethyl 1-(2-fluorophenyl)-5-[3- D-38 LC-MS: (ES,hydrazine (oxetan-3-yloxy)phenyl]-1H- m/z): 383. pyrazole-3-carboxylate(2-Fluorophenyl)- B-28 Methyl 1-(2-fluorophenyl)-5-[3-(2- D-39 LC-MS:(ES, hydrazine methylpropoxy)phenyl]-1H- m/z): 369.pyrazole-3-carboxylate (2-Methyl- B-20 Ethyl 5-(3-cyclobutoxyphenyl)-1-D-40 LC-MS: (ES, phenyl)hydrazine (2-methylphenyl)-1H-pyrazole-3- m/z):376. carboxylate (2-Methyl- B-30 Methyl 5-(3,5-diethoxyphenyl)-1- D-41LC-MS: (ES, phenyl)hydrazine (2-methylphenyl)-1H-pyrazole-3- m/z):381.05. carboxylate (2-Nitrophenyl)- B-14 Methyl5-(1-ethyl-1H-indazol-6- D-42 LC-MS: (ES, hydrazineyl)-1-(2-nitrophenyl)-1H-pyrazole- m/z): 392.30. 3-carboxylateQuinolin-8-yl- B-23 Methyl 5-[3-(2,2-dimethyl- D-43 LC-MS: (ES,hydrazine propoxy)phenyl]-1-(quinolin-8-yl)- m/z): [M + 1] =1H-pyrazole-3-carboxylate 416. C-2 B-29 Methyl 5-(3,5-dimethoxyphenyl)-D-44 LC-MS: (ES, 1-(2-ethoxyphenyl)-1H-pyrazole- m/z): 383.3-carboxylate C-3 B-15 Ethyl 5-(1-ethyl-1H-indazol-6-yl)- D-45 LC-MS:(ES, 1-(1-methyl-1H-indazol-7-yl)-1H- m/z): 414. pyrazole-3-carboxylateC-3 B-20 Ethyl 5-(3-cyclobutoxyphenyl)-1- D-46 LC-MS: (ES,(1-methyl-1H-indazol-7-yl)-1H- m/z): 416. pyrazole-3-carboxylate C-3B-23 Methyl 5-[3-(2,2-dimethyl- D-47 LC-MS: (ES,propoxy)phenyl]-1-(1-methyl-1H- m/z): 419.10.indazol-7-yl)-1H-pyrazole-3- carboxylate C-3 B-24 Methyl5-[3-(cyclobutylmethoxy)phenyl]- D-48 LC-MS: (ES, 1-(1-methyl-1H- m/z):417. indazol-7-yl)-1H-pyrazole-3- carboxylate C-3 B-25 Methyl5-[3-(cyclopropyl- D-49 LC-MS: (ES, methoxy)phenyl]-1-(1-methyl-1H-m/z): 402. indazol-7-yl)-1H-pyrazole-3- carboxylate C-3 B-28 Methyl1-(1-methyl-1H-indazol-7- D-50 LC-MS: (ES, yl)-5-[3-(2-methylpropoxy)-m/z): 405. phenyl]-1H-pyrazole-3- carboxylate C-3 B-29 Methyl5-(3,5-dimethoxyphenyl)- D-51 LC-MS: (ES,1-(1-methyl-1H-indazol-7-yl)-1H- m/z): 393. pyrazole-3-carboxylate C-3B-30 Methyl 5-(3,5-diethoxyphenyl)-1- D-52 LC-MS: (ES,(1-methyl-1H-indazol-7-yl)-1H- m/z): 421.05. pyrazole-3-carboxylate C-5B-23 Methyl 5-[3-(2,2- D-53 LC-MS: (ES, dimethylpropoxy)phenyl]-1-(1-m/z): 432. ethyl-1H-indazol-7-yl)-1H- pyrazole-3-carboxylate C-6 B-2Methyl 5-(3-methoxyphenyl)-1-[2- D-54 LC-MS: (ES,(propan-2-yloxy)phenyl]-1H- m/z): 367. pyrazole-3-carboxylate C-11 B-23Methyl 1-(1,3-dimethyl-1H- D-55 LC-MS: (ES,indazol-7-yl)-5-[3-(2,2-dimethyl- m/z): 433.3.propoxy)phenyl]-1H-pyrazole-3- carboxylate C-12 B-23 Methyl5-[3-(2,2-dimethyl- D-56 LC-MS: (ES, propoxy)phenyl]-1-(1-methyl-1H-m/z): 420. 1,2,3-benzotriazol-7-yl)-1H- pyrazole-3-carboxylate C-13 B-37Methyl 1-[(2-chlorophenyl)- D-57 LC-MS: (ES, methyl]-5-(1-methyl-1H-1,3-m/z): [M + 1] = benzodiazol-6-yl)-1H-pyrazole-3- 381. carboxylateAr₁NHNH₂ Diketone Product (4-Nitro- B-28Methyl-5-[3-(2-methylpropoxy)phenyl]-1-[(4- D-58 phenyl)-nitrophenyl)methyl]-1H-pyrazole-3-carboxylate hydrazine (Pyridin-3-yl)-B-2 Methyl 5-(3-methoxyphenyl)-1-(pyridin-3-yl)-1H- D-59 hydrazinepyrazole-3-carboxylate C-13 B-1 Methyl 1-[(2-chlorophenyl)methyl]-5-(2-D-60 methoxyphenyl)-1H-pyrazole-3-carboxylate C-13 B-10 Methyl5-(4-bromothien-2-yl)-1-[(2-chloro- D-61phenyl)methyl]-1H-pyrazole-3-carboxylate C-13 B-35 Methyl1-[(2-chlorophenyl)methyl]-5-[5-(2- D-62methylpropoxy)thien-2-yl]1H-pyrazole-3- carboxylate C-13 B-36 Methyl1-[(2-chlorophenyl)-5-[2-(2-methyl- D-63propyl)-1,3-oxazol-5-yl]-1H-pyrazole-3- carboxylate C-13 B-39 Methyl1-[(2-chlorophenyl)methyl]-5-[2-(2- D-64methylpropoxy)-1,3-thiazol-5-yl]-1H-pyrazole-3- carboxylate

The following substituted 3-pyrazolecarboxylic esters were obtained fromcondensation of various methyl 4-aryl-2,4-dioxobutanoates with(2-chlorophenyl) hydrazine:

TABLE 8 Pyrazole synthesis with 2-chlorophenyl hydrazine. DiketoneProduct Spectral B-2 Methyl 5-(3-methoxyphenyl)-1-(2- D-65 LC-MS: (ES,methylphenyl)-1H-pyrazole-3-carboxylate m/z): 322. (This product fromreaction with 2-methyl hydrazine) B-3 Methyl1-(2-chlorophenyl)-5-[3-(oxetan-3-yl- D-66 LC-MS: (ES,methoxy)phenyl]-1H-pyrazole-3-carboxylate m/z): 399.0 B-5 Methyl1-(2-chlorophenyl)-5-(pyridin-2-yl)- D-67 LC-MS: (ES,1H-pyrazole-3-carboxylate m/z): 314.20. B-12 Ethyl1-(2-chlorophenyl)-5-(1-methyl-1H- D-68 LC-MS: (ES,indazol-6-yl)-1H-pyrazole-3-carboxylate m/z): 381. B-14 Methyl1-(2-chlorophenyl)-5-(1-ethyl-1H- D-69 LC-MS: (ES,indazol-6-yl)-1H-pyrazole-3-carboxylate m/z): 381. B-20 Ethyl1-(2-chlorophenyl)-5-(3-cyclobutoxy- D-70 LC-MS: (ES,phenyl)-1H-pyrazole-3-carboxylate m/z): 396. B-21 Ethyl1-(2-chlorophenyl)-5-[3-(oxetan-3- D-71 LC-MS: (ES,yloxy)phenyl]-1H-pyrazole-3-carboxylate m/z): 398.95. B-22 Methyl1-(2-chlorophenyl)-5-(3- D-72 LC-MS: (ES,cyclopropoxyphenyl)-1H-pyrazole-3- m/z): 369.25. carboxylate B-23 Methyl1-(2-chlorophenyl)-5-[3-(2,2- D-73 LC-MS: (ES,dimethylpropoxy)phenyl]-1H-pyrazole-3- m/z): 398.95. carboxylate B-24Methyl 1-(2-chlorophenyl)-5-[3-(cyclobutyl- D-74 LC-MS: (ES,methoxy)phenyl]-1H-pyrazole-3-carboxylate m/z): 396.95. B-28 Methyl1-(2-chlorophenyl)-5-[3-(2-methyl- D-75propoxy)phenyl]-1H-pyrazole-3-carboxylate B-29 Methyl1-(2-chlorophenyl)-5-(3,5-dimethoxy- D-76 LC-MS: (ES,phenyl)-1H-pyrazole-3-carboxylate m/z): 373. B-30 Methyl1-(2-chlorophenyl)-5-(3,5-diethoxy- D-77 LC-MS: (ES,phenyl)-1H-pyrazole-3-carboxylate m/z): 401.3. B-40 Ethyl[5-benzyl-1-[(2-chlorophenyl)methyl]- D-78 1H-pyrazole-3-carboxylate

The following substituted 3-pyrazolecarboxylic esters were obtained fromcondensation of Int. B-22 with various substituted hydrazines:

TABLE 9 Pyrazole synthesis with methyl 4-(3-cyclopropoxyphenyl)-2,4-dioxobutanoate (Int. B-22). ArNHNH₂, solvent Product Spectral(2-Fluoro- Methyl 5-(3-cyclopropoxyphenyl)-1-(2- D-79 LC-MS:phenyl)hydrazine fluorophenyl)-1H-pyrazole-3-carboxylate (ES, m/z):hydrochloride, EtOH 353.0. (2-Bromophenyl)- Methyl1-(2-bromophenyl)-5-(3-cyclo- D-80 LC-MS: hydrazine, MeOHpropoxyphenyl)-1H-pyrazole-3- (ES, m/z): carboxylate 413.(2-Bromo-4-fluoro- Methyl 1-(2-bromo-4-fluorophenyl)-5-(3- D-81 LC-MS:phenyl)hydrazine, cyclopropoxyphenyl)-1H-pyrazole-3- (ES, m/z): MeOHcarboxylate 430.90. (2,4-Dichloro- Methyl5-(3-cyclopropoxyphenyl)-1-(2,4- D-82 LC-MS: phenyl)hydrazine,dichlorophenyl)-1H-pyrazole-3- (ES, m/z): MeOH carboxylate 402.95.(2,5-Dichloro- Methyl 5-(3-cyclopropoxyphenyl)-1-(2,5- D-83 LC-MS:phenyl)hydrazine, dichlorophenyl)-1H-pyrazole-3- (ES, m/z): MeOHcarboxylate 402.90. [2-(Difluoro- Methyl 5-(3-cyclopropoxyphenyl)-1-[2-D-84 LC-MS methoxy)phenyl]- (difluoromethoxy)phenyl]-1H-pyrazole-3- (ES,m/z): hydrazine, carboxylate 401 CF₃COOH/MeOH (2-Ethoxyphenyl)- Methyl5-(3-cyclopropoxyphenyl)-1-(2- D-85 LC-MS: hydrazine, MeOHethoxyphenyl)-1H-pyrazole-3-carboxylate (ES, m/z): 378.(2-Methoxyphenyl)- Methyl 5-(3-cyclopropoxyphenyl)-1-(2- D-86 LC-MS:hydrazine methoxyphenyl)-1H-pyrazole-3- (ES, m/z): carboxylate 364.9.(2-Methylphenyl)- Methyl 5-(3-cyclopropoxyphenyl)-1-(2- D-87 LC-MShydrazine dihydro- methylphenyl)-1H-pyrazole-3- (ES, m/z): chloride,MeOH carboxylate 349. (2-Nitrophenyl)- Methyl5-(3-cyclopropoxyphenyl)-1-(2- D-88 LC-MS: hydrazine, EtOHnitrophenyl)-1H-pyrazole-3-carboxylate (ES, m/z): 380. (2-(Propan-2-yl)-Methyl 5-(3-cyclopropoxyphenyl)-1-[2- D-89 phenyl)hydrazine(propan-2-yl)phenyl]-1H-pyrazole-3- HCl, MeOH carboxylate[2-(Trifluoromethyl)- Methyl 5-(3-cyclopropoxyphenyl)-1-[2- D-90 LC-MS:phenyl]hydrazine (trifluoromethyl)phenyl]-1H-pyrazole-3- (ES, m/z):(HCl)₂, MeOH carboxylate 403. C-3, MeOH Methyl5-(3-cyclopropoxyphenyl)-1-(1- D-91 LC-MSmethyl-1H-indazol-7-yl)-1H-pyrazole-3- (ES, m/z): carboxylate 389 C-4,MeOH Methyl 5-(3-cyclopropoxyphenyl)-1-(1- D-92 LC-MS:methyl-1H-indazol-4-yl)-1H-pyrazole-3- (ES, m/z): carboxylate 388. C-5,MeOH Methyl 5-(3-cyclopropoxyphenyl)-1-(1- D-93 LC-MS:ethyl-1H-indazol-7-yl)-1H-pyrazole-3- (ES, m/z): carboxylate 402. C-7,MeOH Methyl 5-(3-cyclopropoxyphenyl)-1-(1H- D-94 LC-MS:indazol-4-yl)-1H-pyrazole-3-carboxylate (ES, m/z): 375.1. C-8, MeOHMethyl 5-(3-cyclopropoxyphenyl)-1-(1H- D-95 LC-MS:indazol-7-yl)-1H-pyrazole-3-carboxylate (ES, m/z): 375. C-9, MeOH Methyl5-(3-cyclopropoxyphenyl)-1-(3- D-96 LC-MS:methyl-1H-indazol-4-yl)-1H-pyrazole-3- (ES, m/z): carboxylate 388.95.C-10, MeOH Methyl 5-(3-cyclopropoxyphenyl)-1-(1- D-97 LC-MS:methyl-1H-1,3-benzodiazol-7-yl)-1H- (ES, m/z): pyrazole-3-carboxylate389.0.

Intermediate E-1: 1-(Bromomethyl)-2-ethoxybenzene

To a solution of (2-ethoxyphenyl)methanol (15.2 g, 99.87 mmol, 1.00equiv) and CBr₄ (50.1 g, 150.00 mmol, 1.50 equiv) in CH₂Cl₂ (200 mL),was added PPh3 (39.45 g, 150.41 mmol, 1.50 equiv), in portions at 0° C.The resulting solution was stirred for 16 h at rt, concentrated undervacuum, and purified with silica gel chromatography using withEtOAc/petroleum ether (1:10) to afford 14 g (65%) of the title compoundas a colorless oil. ¹H-NMR: (CDCl₃, ppm): δ: 7.51-7.25 (m, 1H),7.06-6.86 (m, 1H), 4.65 (s, 1H), 4.16 (q, J=7.0 Hz, 1H), 1.53 (t, J=7.0Hz, 1H).

Intermediate E-2: 1-(Bromomethyl)-2-cyclopropoxybenzene

Methyl 2-cyclopropoxybenzoate

To a mixture of methyl 2-hydroxybenzoate (5.0 g, 32.86 mmol, 1.00 equiv)Cs₂CO₃ (32 g, 98.21 mmol, 3.00 equiv) in DMA (100 mL) was added dropwisebromocyclopropane (39.8 g, 328.99 mmol, 10.00 equiv) with stirring atrt. The resulting solution was stirred for 16 h at 130° C., cooled,diluted with 200 mL of EtOAc, washed with 2×200 mL of water and 2×200 mLof brine, dried over Na₂SO₄, and concentrated under vacuum. The residuewas purified by silica gel chromatography using EtOAc/petroleum ether(1:6) to afford 1.6 g (25%) of the title compound as a yellow oil.LC-MS: (ES, m/z): 193. 1H NMR (400 MHz, CDCl₃) δ 7.80 (dd, J=7.8, 1.8Hz, 1H), 7.49 (ddd, J=8.9, 7.3, 1.8 Hz, 1H), 7.38 (dd, J=8.4, 1.1 Hz,1H), 7.01 (td, J=7.5, 7.5, 1.2 Hz, 1H), 3.89 (s, 3H), 3.83 (tt, J=5.9,5.9, 3.2, 3.2 Hz, 1H), 0.86 (m, 4H).

(2-Cyclopropoxyphenyl)methanol

To a solution of methyl 2-cyclopropoxy-benzoate (1.5 g, 7.80 mmol, 1.00equiv) in THF (100 mL) was added LiAlH₄ (594 mg, 15.65 mmol, 2.00equiv), in portions at 0° C. The resulting mixture was stirred for 2 hat 0° C. in an ice/salt bath, then quenched by the addition of Na₂SO₄/10H₂O. The solids were removed by filtration. The resulting solution wasconcentrated under vacuum and purified with silica gel chromatographyusing EtOAc/petroleum ether (1:5) to afford 750 mg (59%) of the titlecompound as a yellow oil. LC-MS: (ES, m/z): 187. ¹H NMR: (400 MHz,CDCl₃) δ 7.30 (m, 3H), 6.98 (tdd, J=7.5, 7.5, 3.7, 1.5 Hz, 1H), 4.65 (s,2H), 3.80 (m, 1H), 0.82 (m, 4H).

1-(Bromomethyl)-2-cyclopropoxybenzene

To a solution of (2-cyclopropoxy-phenyl)methanol (750 mg, 4.57 mmol,1.00 equiv) and CBr₄ (3.06 g, 9.16 mmol, 2.00 equiv) in CH₂C₁₂ (30 mL)was added PPh3 (2.40 g, 9.15 mmol, 2.00 equiv) in portions at 0° C. Theresulting solution was stirred for 2 h at room temperature, concentratedunder vacuum, and purified with silica gel chromatography using withEtOAc/petroleum ether (1:5) to afford 1.0 g (96%) of the title compoundas colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.30 (m, 3H), 6.96 (dt,J=7.6, 1.8, 1.8 Hz, 1H), 4.52 (s, 2H), 3.84 (m, 1H), 0.83 (m, 4H).

Intermediate E-3 2-(bromomethyl)-1-ethoxy-3-fluorobenzene

Methyl 2-ethoxy-6-fluorobenzoate

A mixture of methyl 2-fluoro-6-hydroxy-benzoate (500 mg, 2.94 mmol, 1.00equiv), K₂CO₃ (811 mg, 5.87 mmol, 2.00 equiv), EtI (911 mg, 5.84 mmol,2.00 equiv) in DMF (15 mL) was stirred overnight at 80° C., cooled tort, and extracted with 3×20 mL of EtOAc. The combined organic layerswere dried over Na₂SO₄ and concentrated under vacuum to afford 500 mg(86%) of the title compound as light yellow oil.

LC-MS: (ES, m/z): 199.3. ¹H NMR (300 MHz, CDCl₃) δ 7.29 (m, 1H), 6.70(m, 2H), 4.08 (q, J=7.0, 7.0, 7.0 Hz, 2H), 3.92 (s, 3H), 1.40 (t, J=7.0,7.0 Hz, 3H).

2-Ethoxy-6-fluorobenzoic Acid

A solution of the product from the previous step (2.6 g, 13.12 mmol,1.00 equiv) and NaOH (2 g, 50.00 mmol, 4.00 equiv) in MeOH/H₂O (20/10mL) was stirred overnight at 40° C. The pH value of the solution wasadjusted to 5 with 1 M HCl. The resulting solution was extracted with3×50 mL of EtOAc. The combined organic layers were dried over Na₂SO₄ andconcentrated under vacuum to afford 1.9 g (79%) of the title compound asa colorless oil.

LC-MS: (ES, m/z): 185.3.

(2-Ethoxy-6-fluorophenyl)methanol

To a solution of the product from the previous step (1.9 g, 10.32 mmol,1.00 equiv) and isobutyl chloroformate (2.1 g, 15.38 mmol, 1.50 equiv)in THF (50 mL) at 0° C. was added TEA (4.5 mL, 3.00 equiv). The reactionwas stirred for 2 h at 0° C., then filtered. To the filtrate was addedNaBH₄ (780 mg, 20.62 mmol, 2.00 equiv) at 0° C. The resulting solutionwas stirred for 3 h at room temperature. The reaction was then quenchedby the addition of 10 mL of water/ice. The resulting solution wasextracted with 3×50 mL of EtOAc. The combined organic layers were driedover Na₂SO₄, concentrated under vacuum, and purified with silica gelchromatography using EtOAc/petroleum ether (2/1) to afford 0.7 g (40%)of the title compound as a light yellow oil.

¹H NMR (300 MHz, DMSO) δ 7.27 (td, J=8.3, 8.3, 7.0 Hz, 1H), 6.77 (m,2H), 4.75 (t, J=5.5, 5.5 Hz, 1H), 4.48 (dd, J=5.5, 1.9 Hz, 2H), 4.06 (q,J=7.0, 7.0, 7.0 Hz, 2H), 1.35 (t, J=6.9, 6.9 Hz, 3H).

2-(Bromomethyl)-1-ethoxy-3-fluorobenzene

A solution of the product from the previous step (700 mg, 4.11 mmol,1.00 equiv), PPh3 (2.16 g, 8.24 mmol, 2.00 equiv), and CBr₄ (2.7 g, 2.00equiv) in CH₂C₁₂ (30 mL) was stirred for 2 h at rt. The resultingsolution was extracted with 3×30 mL of EtOAc. The combined organiclayers were dried over Na₂SO₄, concentrated under vacuum, and purifiedwith silica gel chromatography using EtOAc/petroleum ether (5/1) toafford 0.4 g (42%) of the title compound as a light yellow oil.

¹H NMR (300 MHz, CDCl₃) δ 7.24 (m, 1H), 6.69 (m, 2H), 4.67 (dd, J=32.8,1.5 Hz, 2H), 4.13 (qd, J=7.0, 7.0, 7.0, 2.5 Hz, 2H), 1.48 (td, J=7.0,6.9, 3.2 Hz, 3H).

Intermediate E-4 1-(Bromomethyl)-2-(propan-2-yloxy)benzene

[2-(Propan-2-yloxy)phenyl]methanol

To a solution of 2-(hydroxymethyl)phenol (2 g, 16.11 mmol, 1.00 equiv)in DMF (10 mL) was added sequentially 2-iodopropane (5.48 g, 32.24 mmol,2.00 equiv) then Cs₂CO₃ (10.5 g, 32.23 mmol, 2.00 equiv). The resultingsolution was stirred overnight at 85° C. The reaction mixture was cooledto room temperature. The resulting solution was extracted with 3×50 mLof EtOAc, and the organic layers were combined, dried over anhydrousNa₂SO₄, and concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/hexane (1/4). This resulted in the titlecompound as a light yellow oil (2.1 g, 78%).

1-(Bromomethyl)-2-(propan-2-yloxy)benzene

To a solution of the product from the previous step (3 g, 18.05 mmol,1.00 equiv) in CH₂Cl₂ (50 mL) were added sequentially CBr₄ (12.84 g,36.17 mmol, 2.00 equiv) and PPh3 (9.48 g, 36.14 mmol, 2.00 equiv) in anice bath. The resulting solution was stirred for 5 h at roomtemperature. The resulting solution was extracted with 3×100 mL ofCH₂Cl₂, and the organic layers were combined, dried over anhydrousNa₂SO₄, and concentrated under vacuum. The residue was applied onto asilica gel column with EtOAc/hexane (1/4). This resulted in the titlecompound as a light yellow oil (1.6 g, 39%).

The following alkylating agents were reacted with pyrazoles as disclosedbelow:

-   Intermediate E-5 1-(Chloromethyl)-2-nitrobenzene-   Intermediate E-6 1-Bromo-2-(bromomethyl)-benzene-   Intermediate E-7 1-(Bromomethyl)-2-chlorobenzene-   Intermediate E-8 2-(Bromomethyl)-1-fluoro-3-nitrobenzene-   Intermediate E-9 (2-Bromoethyl)benzene-   Intermediate E-10 1-(Chloromethyl)-2-chlorobenzene-   Intermediate E-11 2-(Bromomethyl)pyridine-   Intermediate E-12 7-(Bromomethyl)-1-methyl-1H-indazole-   Intermediate E-13 1-bromo-2-methylpropane-   Intermediate E-14 4-(bromomethyl)tetrahydropyran

Intermediate D-98: Methyl1-[(3-chlorophenyl)methyl]-5-phenyl-1H-pyrazole-3-carboxylate

To a suspension of methyl 5-phenyl-1H-pyrazole-3-carboxylate (1) (1.0 g,4.94 mmol) in toluene was added NaH (60%) (0.394 g, 9.88 mmol)portionwise under N₂ at room temperature, and stirring was continued for30 min. To the above mixture a solution of 3-chlorobenzyl bromide (0.96ml, 7.42 mmol) in toluene (3 mL) was added dropwise at 60° C. Thereaction mixture was stirred at 110° C. for 16 h. The mixture was cooledto room temperature and quenched with aq. NH₄Cl solution. The mixturewas partitioned with EtOAc (100 mL) and the organic layer was separated.The EtOAc layer was washed with brine (2×25 mL) and dried over Na₂SO₄,and the solvent was evaporated. The residue was chromatographed overSiO₂ (ISCO CombiFlash® Rf 200) using 0-50% gradient of EtOAc in hexaneto afford title compound (1.2 g, 75%). ¹H NMR (CDCl₃, 400 MHz) δ 3.95(s, 3H), 5.36 (s, 2H), 6.85-6.92 (m, 2H), 6.95-6.99 (m, 1H), 7.17-7.29(m, 4H). 7.35-7.48 (m, 3H).

Intermediate D-99: Methyl1-[(2-cyclopropoxyphenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

To a solution of Int. D-3 (793 mg, 3.41 mmol, 1.00 equiv) in toluene (10mL) was added NaH (164 mg, 6.83 mmol, 2.00 equiv). The resultingsolution was stirred at rt for 30 min, then warmed to 60° C. To this wasadded a solution of Int. E-2 (1 g, 4.40 mmol, 1.30 equiv) in toluene (10mL). The resulting solution was stirred at 60° C. for 1 h, then thesolution was heated to 110° C. and stirred for 6 h at this temperature.The reaction mixture was then cooled to rt, quenched by the addition of10 mL of water/ice, and extracted with 3×100 mL of EtOAc. The combinedorganic layers were dried over Na₂SO₄, and concentrated under vacuum,and purified with silica gel column using EtOAc/hexane (1/3) to afford 1g (77%) of the title compound as a yellow oil. LC-MS: (ES, m/z): 379.

Intermediate D-100: Methyl1-[(2-chlorophenyl)methyl]-5-(3,5-dimethoxyphenyl)-1H-pyrazole-3-carboxylate

To a solution of methyl Int. D-21 (1.0 g, 3.81 mmol, 1.00 equiv) intoluene (50 mL) was added NaH (304 mg, 7.60 mmol, 2.00 equiv) inportions at rt. The mixture was stirred at rt for 30 min, then Int. E-7(1.56 g, 7.59 mmol, 2.00 equiv) was added dropwise with stirring at 60°C. The resulting solution was stirred for 1 h at 60° C., then warmed to110° C. and stirred for an additional 3 h. The reaction was thenquenched by the addition of water/ice. The resulting solution wasextracted with 200 mL of EtOAc, and the combined organic layers werewashed with 2×100 mL of brine, dried over Na₂SO₄, concentrated undervacuum, and purified with silica gel chromatography usingEtOAc/petroleum ether (1:3) to afford 800 mg (54%) of the title compoundas a colorless oil. LC-MS: (ES, m/z): 387. ¹H-NMR: (CDCl₃, ppm): δ:7.42-7.29 (m, 1H), 7.29-7.13 (m, 2H), 6.97 (s, 1H), 6.77-6.67 (m, 1H),6.42 (dd, J=30.5, 2.3 Hz, 3H), 5.55 (s, 2H), 3.97 (d, J=1.0 Hz, 3H),3.69-3.60 (m, 6H).

The following substituted pyrazoles were obtained from alkylation withan alkyl halide:

TABLE 10 Pyrazole alkylation. Alkyl Pyrazole halide Product Spectral D-2E-1 Methyl 5-(3-cyclopropoxyphenyl)-1-[(2- D-101 LC-MS: (ES, m/z): 393.ethoxyphenyl)methyl]-1H-pyrazole-3- carboxylate D-2 E-2 Methyl5-(3-cyclopropoxyphenyl)-1-[(2- D-102 LC-MS: (ES, m/z): 394.nitrophenyl)methyl]-1H-pyrazole-3- carboxylate D-2 E-6 Methyl1-[(2-bromophenyl)methyl]-5-(3- D-103 LC-MS: (ES, m/z): 429.2.cyclopropoxyphenyl)-1H-pyrazole-3- carboxylate D-5 E-7 Methyl1-[(2-chlorophenyl)methyl]-5-(2,3- D-104 LC-MS: (ES, m/z): 385.dihydro-1,4-benzodioxin-6-yl)-1H-pyr- azole-3-carboxylate D-6 E-7 Methyl5-(2H-1,3-benzodioxol-5-yl)-1-[(2- D-105 LC-MS: (ES, m/z): 371.chlorophenyl)methyl]-1H-pyrazole-3- carboxylate D-7 E-7 Methyl1-[(2-chlorophenyl)methyl]-5-(1- D-106 LC-MS: (ES, m/z): 331.methyl-1H-pyrazol-4-yl)-1H-pyrazole-3- carboxylate D-8 E-7 Ethyl5-(1-benzothiophen-2-yl)-1-[(2- D-107 LC-MS: (ES, m/z): 397.chlorophenyl)methyl]-1H-pyrazole-3- carboxylate D-9 E-7 Ethyl1-[(2-chlorophenyl)methyl]-5-(1- D-108 LC-MS: (ES, m/z): 393.methyl-1H-indol-6-yl)-1H-pyrazole-3- carboxylate D-10 E-1 Ethyl1-[(2-ethoxyphenyl)methyl]-5-(1- D-109 LC-MS: (ES, m/z): 404.methyl-1H-indazol-6-yl)-1H-pyrazole-3- carboxylate D-10 E-7 Ethyl1-[(2-chlorophenyl)methyl]-5-(1- D-110 LC-MS: (ES, m/z): 394.methyl-1H-indazol-6-yl)-1H-pyrazole-3- carboxylate D-11 E-7 Methyl1-[(2-chlorophenyl)methyl]-5-(1- D-111 LC-MS: (ES, m/z): 395.ethyl-1H-indazol-6-yl)-1H-pyrazole-3- carboxylate D-11 E-11 Methyl5-(1-ethyl-1H-indazol-6-yl)-1- D-112 LC-MS: (ES, m/z): 362.3.([pyridin-2-yl]methyl)-1H-pyrazole-3- carboxylate D-12 E-1 Methyl5-(3-chloro-5-methoxyphenyl)-1- D-113 LC-MS: (ES, m/z): 401.[(2-ethoxyphenyl)methyl]-1H-pyrazole-3- carboxylate D-13 E-7 Ethyl1-[(2-chlorophenyl)methyl]-5-(1- D-114 LC-MS: (ES, m/z): 394.methyl-1H-indazol-5-yl)-1H-pyrazole-3- carboxylate D-11 E-1 Methyl1-[(2-ethoxyphenyl)methyl]-5-(1- D-115 LC-MS: (ES, m/z): 404.ethyl-1H-indazol-6-yl)-1H-pyrazole-3- carboxylate D-14 E-7 Ethyl1-[(2-chlorophenyl)methyl]-5-(1- D-116 LC-MS: (ES, m/z): 381.methyl-1H-indazol-4-yl)-1H-pyrazole-3- carboxylate D-15 E-7 Methyl1-[(2-chlorophenyl)methyl]-5-(1- D-117 LC-MS: (ES, m/z): 396.ethyl-1H-1,2,3-benzotriazol-6-yl)-1H- pyrazole-3-carboxylate D-16 E-1Ethyl 5-(3-cyclobutoxyphenyl)-1-[(2-eth- D-118 LC-MS: (ES, m/z): 421.oxyphenyl)methyl]-1H-pyrazole-3- carboxylate D-16 E-6 Ethyl1-[(2-bromophenyl)methyl]-5-(3- D-119 LC-MS: (ES, m/z): 454.cyclobutoxyphenyl)-1H-pyrazole-3- carboxylate D-17 E-12 Methyl5-[3-(2,2-dimethylpropoxy)- D-120 LC-MS: (ES, m/z): 433.3.phenyl]-1-[(1-methyl-1H-indazol-7- yl)methyl]-1H-pyrazole-3-carboxylateD-18 E-1 Methyl 5-(3-ethoxyphenyl)-1-[(2-ethoxy- D-121 LC-MS: (ES, m/z):394. phenyl)methyl]-1H-pyrazole-3-carboxylate D-19 E-7 Methyl5-[3-(benzyloxy)phenyl]-1-[(2- D-122 LC-MS: (ES, m/z): 433.05.chlorophenyl)methyl]-1H-pyrazole-3- carboxylate D-20 E-11 Methyl5-[3-(2-methylpropoxy)phenyl]-1- D-123 LC-MS: (ES, m/z): 366.([pyridin-2-yl]methyl)-1H-pyrazole-3- carboxylate D-21 E-1 Methyl5-(3,5-dimethoxyphenyl)-1-[(2- D-124 LC-MS: (ES, m/z): 397ethoxyphenyl)methyl]-1H-pyrazole-3- carboxylate D-21 E-95-(3,5-Dimethoxyphenyl)-1-(2-phenyl- D-125 LC-MS: (ES, m/z): 366.ethyl)-1H-pyrazole-3-carboxylate D-21 E-3 Methyl5-(3,5-dimethoxyphenyl)-1-[(2- D-126 LC-MS: (ES, m/z): 415.10.ethoxy-6-fluorophenyl)methyl]-1H- pyrazole-3-carboxylate D-21 E-11Methyl 5-(3,5-dimethoxyphenyl)-1- D-127 LC-MS: (ES, m/z): 354.([pyridin-2-yl]methyl)-1H-pyrazole-3- carboxylate D-22 E-1 Methyl5-(3,5-diethoxyphenyl)-1-[(2- D-128 LC-MS: (ES, m/z): 425.1.ethoxyphenyl)methyl]-1H-pyrazole-3- carboxylate D-22 E-7 Methyl1-[(2-chlorophenyl)methyl]-5-(3,5- D-129 LC-MS: (ES, m/z): 415.15.diethoxyphenyl)-1H-pyrazole-3- carboxylate D-23 E-1 Methyl5-(3-ethoxy-5-methoxyphenyl)-1- D-130 LC-MS: (ES, m/z): 411.[(2-ethoxyphenyl)methyl]-1H-pyrazole-3- carboxylate D-24 E-10 Ethyl1-[(2-chlorophenyl)methyl]-5-[2- D-131 LC-MS: (ES, m/z): 389.(propan-2-yloxy)-1,3-oxazol-5-yl]-1H- pyrazole-3-carboxylate D-25 E-7Methyl 1-[(2-chlorophenyl)methyl]-5-[1,3- D-132 LC-MS: (ES, m/z): 401dimethyl-1H-thieno[2,3-c]pyrazol-5-yl]- 1H-pyrazole-3-carboxylate AlkylPyrazole Halide Product D-3 E-8 Methyl1-[(2-fluoro-6-nitrophenyl)methyl]-5-(3- D-133methoxyphenyl)-1H-pyrazole-3-carboxylate D-3 E-4 Methyl5-(3-methoxyphenyl)-1-[[2-(propan-2- D-134yloxy)phenyl]methyl]-1H-pyrazole-3-carboxylate D-3 E-13 Methyl5-(3-methoxyphenyl)-1-(2-methylpropyl)- D-135 1H-pyrazole-3-carboxylateD-3 E-14 Methyl 5-(3-methoxyphenyl)-1-([oxan-4- D-136yl]methyl)-1H-pyrazole-3-carboxylate D-4 E-7 Methyl1-[(2-chlorophenyl)methyl]-5-(3- D-137nitrophenyl)-1H-pyrazole-3-carboxylate D-26 E-7 Methyl1-[(2-chlorophenyl)methyl]-5-[3-[(propan- D-1382-yl)carbamoyl]phenyl]-1H-pyrazol-3-carboxylate

Intermediate D-139: Methyl1-[(2,6-dimethoxyphenyl)methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazole-3-carboxylate

To a solution of Int. D-20 (1.37 g, 4.99 mmol, 1.00 equiv) in THF (50mL) under N₂ at 0° C. was added (2,6-dimethoxyphenyl)methanol (1.26 g,7.49 mmol, 1.50 equiv) followed by PPh₃ (1.81 g, 6.90 mmol, 1.30 equiv).Subsequently DIAD (1.75 g, 8.65 mmol, 1.50 equiv) was added dropwise andthe resulting solution was stirred for 16 h at 25° C. The residue wasapplied onto a silica gel column with EtOAc/petroleum ether (1:19). Thisresulted in the title compound as a yellow solid (890 mg, 42%).

Intermediate D-140: Methyl1-[(3-chloropyridin-2-yl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

(3-Chloropyridin-2-yl)methanol

To a solution of 3-chloropyridine-2-carboxylic acid (2.1 g, 13.33 mmol,1.00 equiv) in THF (40 mL) was added Et₃N (2.7 g, 26.68 mmol, 2.00equiv), followed by the addition of chloro(propan-2-yloxy)methanone(2.45 g, 19.99 mmol, 1.50 equiv) dropwise with stirring at 0° C. Thesolution was stirred for 1 h at room temperature. The solid was removedby filtration. To the filtrate was added NaBH₄ (1.53 g, 40.44 mmol, 3.00equiv). The resulting solution was stirred for 2 h at rt, then dilutedwith 50 mL of H₂O and extracted with 2×100 mL of EtOAc. The combinedorganic layers were washed with 50 mL of saturated NaCl, dried overNa₂SO₄, concentrated under vacuum, and purified with silica gelchromatography using with EtOAc/petroleum ether (1:6) to afford 0.9 g(47%) of the title compound as a colorless oil.

Methyl1-[(3-chloropyridin-2-yl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

To a solution of the product from the previous step (850 mg, 5.92 mmol,1.00 equiv) in THF (8.5 mL), under N₂, was added Int. D-3 (1.4 g, 6.03mmol, 1.00 equiv) and Ph₃P (3.1 g, 11.82 mmol, 2.00 equiv), followed bythe addition of DIAD (1.8 g, 8.91 mmol, 1.50 equiv) dropwise withstirring at 0° C. The resulting solution was stirred for 5 h at rt,diluted with 30 mL of H₂O, and extracted with 2×50 mL of EtOAc. Thecombined organic layers were washed with 20 mL of saturated NaCl, driedover Na₂SO₄, concentrated under vacuum, and purified with silica gelchromatography using EtOAc/petroleum ether (1:10) to afford 1.7 g (80%)of the title compound as a white solid. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.90(s, 1H), 8.35 (dd, J=4.7, 1.5 Hz, 1H), 7.99 (dd, J=8.1, 1.5 Hz, 1H),7.51 (s, 1H), 7.45 (dt, J=7.7, 1.2 Hz, 1H), 7.41 (dd, J=2.6, 1.5 Hz,1H), 7.36-7.30 (m, 1H), 6.91 (ddd, J=8.2, 2.7, 1.0 Hz, 1H), 5.99 (s,2H), 3.80 (s, 3H), 3.77 (s, 3H).

Intermediate D-141: Methyl1-[[4-(dimethylamino)phenyl]methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazole-3-carboxylate

Methyl1-[(4-aminophenyl)methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazole-3-carboxylate

To a solution of Int. D-58 (2 g, 4.88 mmol, 1.00 equiv) in AcOH/H₂O(100/40 mL) was added Zn (1 g, 15.29 mmol, 3.00 equiv), and theresulting solution was stirred for 5 h at 25° C. The solids werecollected by filtration. The pH value of the solution was adjusted to 7with (sat) NaHCO₃(aq) and the resulting solution was extracted with 200mL of EtOAc. The combined organic layers were concentrated under vacuumto afford 1.5 g (81%) of the title compound as a yellow oil.

Methyl1-[[4-(dimethylamino)phenyl]methyl]-5-[3-(2-methylpropoxy)phenyl]-1H-pyrazole-3-carboxylate

To a solution of the product from the previous step (1.35 g, 3.56 mmol,1.00 equiv) in MeOH (50 mL) was added formaldehyde (5 mL, 1.50 equiv) in30 min. To this was added NaCNBH₃ (800 mg, 12.73 mmol, 3.00 equiv), andthe resulting solution was stirred for 5 min at 25° C. The resultingsolution was extracted with 200 mL of EtOAc, and the combined organiclayers were purified with silica gel chromatography usingEtOAc/petroleum ether (1:7) to afford 810 mg (56%) of the title compoundas a yellow liquid.

Intermediate D-142: Methyl1-[[2-(dimethylamino)-6-fluorophenyl]methyl]-5-(3-methoxyphenyl)-1H-pyrazole-3-carboxylate

Intermediate D-142 was obtained from Int. D-133 by a zincreduction/reduction amination sequence similar to that used to prepareInt. D-141.

Intermediate D-143: Methyl1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazole-3-carboxylate

1-[(2-Chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazole-3-carboxylicAcid

A solution of Int. D-122 (3.2 g, 7.39 mmol, 1.00 equiv) in AcOH/HCl(15/5 mL) was stirred for 2 h at 90° C., then cooled, concentrated undervacuum, and purified with silica gel chromatography usingEtOAc/petroleum ether (2/1) to afford 2 g (82%) of the title compound asa light yellow oil. LC-MS: (ES, m/z): 329.0. ¹H NMR: (300 MHz, DMSO) δ12.83 (s, 1H), 9.72 (s, 1H), 7.46 (m, 1H), 7.29 (m, 3H), 6.81 (m, 5H),5.48 (s, 2H).

Methyl1-[(2-chlorophenyl)methyl]-5-(3-hydroxyphenyl)-1H-pyrazole-3-carboxylate

A solution of the product from the previous step (2 g, 6.08 mmol, 1.00equiv) and H₂SO₄ (1 mL) in MeOH (20 mL) was stirred for 2 h at 65° C.The pH was adjusted to 7 with saturated NaHCO₃. The resulting solutionwas extracted with 3×30 mL of EtOAc, and the combined organic layerswere dried over Na₂SO₄, concentrated under vacuum, and purified withsilica gel chromatography using EtOAc/petroleum ether (2/1) to afford1.7 g (82%) of the title compound as a white solid. LC-MS: (ES, m/z):343.1. 1H NMR: (400 MHz, DMSO) δ 9.74 (s, 1H), 7.46 (m, 1H), 7.31 (m,3H), 6.93 (s, 1H), 6.83 (m, 4H), 5.50 (s, 2H), 3.82 (s, 3H).

Methyl1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazole-3-carboxylate

To a solution of the product from the previous step (1.7 g, 4.96 mmol,1.00 equiv), PPh3 (2.62 g, 9.99 mmol, 2.00 equiv), and(oxetan-3-yl)methanol (870 mg, 9.87 mmol, 2.00 equiv) in THF (30 mL) at−10° C. under an N₂ atmosphere was added DTAD (1.82 g, 9.01 mmol, 1.80equiv). The resulting solution was stirred overnight at rt and extractedwith 3×30 mL of EtOAc. The combined organic layers were dried overNa₂SO₄, concentrated under vacuum, and purified with silica gelchromatography using EtOAc/petroleum ether (1/3) to afford 1.1 g (54%)of the title compound as a white solid. LC-MS: (ES, m/z): 413.1.

Intermediate D-144: Methyl5-(3-cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-7-yl)-1H-pyrazole-3-carboxylate

To a solution of Int. D-95 (600 mg, 1.60 mmol, 1.00 equiv) in CH₂Cl₂ (15mL) was added NaH (128 mg, 5.33 mmol, 2.00 equiv). The solution wasstirred 10 min, then SEMCl (664 mg, 2.50 equiv) was added. The resultingsolution was stirred for 16 h at rt, then quenched by the addition ofwater, and extracted with 2×100 mL of EtOAc. The combined organic layerswere washed with 100 mL of brine, dried over Na₂SO₄, concentrated undervacuum, and purified with silica gel column using EtOAc/petroleum ether(1:2) to afford 300 mg (37%) of the title compound as a yellow oil.LC-MS: (ES, m/z): 504.

Intermediate D-145: Methyl5-(3-cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazole-3-carboxylate

To a solution of Int. D-94 (460 mg, 1.23 mmol, 1.00 equiv) in CH₂Cl₂ (10mL) was added NaH (57.5 mg, 2.40 mmol, 2.00 equiv) at 0° C. Theresulting solution was stirred for 30 min, then SEMCl (253 mg, 0.69mmol, 1.30 equiv) was added. The resulting solution was stirred for 5 hat rt, then quenched with H₂O and extracted with 3×20 mL of EtOAc. Thecombined organic layers were dried over Na₂SO₄, concentrated undervacuum, and purified with silica gel chromatography usingEtOAc/petroleum ether (1/3) to afford 300 mg (48%) of the title compoundas a colorless oil. LC-MS: (ES, m/z): 505.1.

Intermediate D-146: methyl5-(3-cyclopropoxyphenyl)-1-(3-methyl-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazole-3-carboxylate

To a solution of Int. D-96 (500 mg, 1.29 mmol, 1.00 equiv) in CH₂Cl₂ (10mL) was added NaH (62 mg, 2.58 mmol, 2.00 equiv). The resulting solutionwas stirred for 30 min at 0° C., then[2-(chloromethoxy)ethyl]trimethylsilane (278 mg, 1.67 mmol, 1.30 equiv)was added. The resulting solution was stirred for 5 h at rt, thenquenched with H₂O and extracted with 3×20 mL of CH₂Cl₂. The combinedorganic layers were dried over Na₂SO₄, concentrated under vacuum, andpurified with prep-TLC using EtOAc/petroleum ether (1/3) to afford 250mg (36%) of the title compound as a colorless oil. LC-MS: (ES, m/z):519.40.

Intermediate D-147: Ethyl1-[(2-chlorophenyl)methyl]-5-phenoxy-1H-pyrazole-3-carboxylate

Ethyl1-[(2-chlorophenyl)methyl]-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate

A solution of Int. C-13 (4 g, 17.54 mmol, 1.00 equiv) and 1,4-diethyl2-oxo-butanedioate (0 mg, 1.30 equiv) in EtOH (120 mL) was heated toreflux overnight, then concentrated under vacuum. The crude product waspurified using silica gel chromatography using EtOAc/petroleum ether(1:20-1:5), to afford 2.8 g (57%) of the title product as a yellowsyrup.

Ethyl1-[(2-chlorophenyl)methyl]-5-(2-nitrophenoxy)-1H-pyrazole-3-carboxylate

A solution of the product from the previous step (2.8 g, 9.97 mmol, 1.00equiv), 1-fluoro-2-nitrobenzene (2.8 g, 19.84 mmol, 2.00 equiv), andK₂CO₃ (2.7 g, 19.57 mmol, 2.00 equiv) in DMF (20 mL) was stirredovernight at 90° C. The resulting solution was diluted with EtOAc,washed with water and brine, dried over anhydrous Na₂SO₄, andconcentrated under vacuum. The crude product was purified with silicagel chromatography using EtOAc/petroleum ether (1:50-1:10) to afford 0.8g (20%) of the title product as a yellow oil.

Ethyl5-(2-aminophenoxy)-1-[(2-chlorophenyl)methyl]-1H-pyrazole-3-carboxylate

A solution of the product from the previous step (800 mg, 1.99 mmol,1.00 equiv) in AcOH/H₂O (3:1) (8 mL) was stirred over Zn (600 mg, 9.38mmol, 5.00 equiv) for 3 h at 60° C. The solids were removed byfiltration, and the filtrate was concentrated under vacuum. The crudeproduct was purified by silica gel chromatography using EtOAc/petroleumether (1:30-1:5) to afford 540 mg (73%) of the title product as a yellowsolid.

Ethyl 1-[(2-chlorophenyl)methyl]-5-phenoxy-1H-pyrazole-3-carboxylate

To a solution of the product from the previous step (540 mg, 1.45 mmol,1.00 equiv) in THF (15 mL) was added tert-butyl nitrite (450 mg, 4.36mmol, 3.00 equiv). The resulting solution was stirred for 30 min at 60°C., then concentrated under vacuum. The residue was purified withPrep-TLC (EtOAc:PE=1:3) to afford 220 mg (42%) of the title product as asolid.

Intermediate F-1:[1-[(3-Chlorophenyl)methyl]-5-phenyl-1H-pyrazol-3-yl]methanol

A solution of Int. D-98 (0.80 g, 2.45 mmol) in anhydrous THF was cooledto 0° C. To the above mixture LiAlH₄ (0.14 g, 3.67 mmol) was addedportionwise, and stirring was continued at 0° C. for 1.30 h. The mixturewas quenched with water (0.15 mL) and 30% aq. NaOH solution (0.3 mL) at0° C., and stirring was continued for 30 min. The reaction mixture wasfiltered, the filter cake was washed with THF (2×10 mL), and thefiltrates were combined and evaporated to dryness. The residue waschromatographed over SiO₂ (ISCO CombiFlash® Rf 200) using 0-40% gradientof EtOAc in DCM to afford the title product (0.58 g 79%). ¹H NMR (CDCl₃,400 MHz) δ 4.64-4.81 (d, 2H), 5.31 (s, 2H), 6.35 (s, 1H), 6.86-6.94 (m,1H), 6.98-7.05 (m, 1H), 7.19-7.23 (m, 2H), 7.26-7.35 (m, 2H), 7.39-7.46(m 3H).

The following substituted 3-(hydroxymethyl)pyrazoles were obtained fromLiAlH₄ reduction of the corresponding methyl esters:

TABLE 11 LiAlH₄ reduction of pyrazole carboxylic esters. Ester ProductSpectral D-57 [1-[(2-chlorophenyl)methyl]-5-(1-methyl-1H-1,3- F-2 LC-MS:(ES, m/z): benzodiazol-6-yl)-1H-pyrazol-3-yl]methanol [M + 1] = 353.D-59 [5-(3-Methoxyphenyl)-1-pyridin-3-yl)-1H- F-3 pyrazol-3-yl]methanolD-65 [5-(3-Methoxyphenyl)-1-(2-methylphenyl)-1H- F-4pyrazol-3-yl]methanol D-117[1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1H-1,2,3- F-5 LC-MS: (ES, m/z):368. benzotriazol-6-yl)-1H-pyrazol-3-yl]methanol D-132[1-[(2-chlorophenyl)methyl]-5-[1,3-dimethyl-1H- F-6 LC-MS: (ES, m/z):373. thieno[2,3-c]pyrazol-5-yl]-1H-pyrazol-3- yl]methanol D-137[1-[(2-chlorophenyl)methyl]-5-(3-nitrophenyl)- F-71H-pyrazole-3-yl]methanol

Intermediate F-8:[1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methanol

(iii) To a solution of Int. D-28 (5.5 g, 15.41 mmol, 1.00 equiv) in THF(100 mL) was added LiBH₄ (20 mL) dropwise with stirring at 0° C. in 5min. The resulting solution was stirred for 16 h at room temperature.The reaction was then quenched by the addition of 5 mL of water, dilutedwith 200 mL of H₂O, extracted with 2×200 mL of EtOAc, and the organiclayers were combined. The resulting mixture was washed with 1×100 mL ofbrine then dried over anhydrous Na₂SO₄ and concentrated under vacuum.The residue was applied onto a silica gel column with EtOAc/petroleumether (1:8). This resulted in the title compound as a white solid (4.3g, 85%).

The following substituted 3-(hydroxymethyl)pyrazoles were obtained fromLiBH₄ reduction of the corresponding methyl esters:

TABLE 12 LiBH₄ reduction of pyrazole carboxylic esters. Ester ProductSpectral D-29 [5-[3-(2-Methylpropoxy)phenyl]-1-phenyl-1H- F-9 LC-MS:(ES, m/z): 323. pyrazol-3-yl]methanol D-30[1-(2-Bromophenyl)-5-(1-ethyl-1H-indazol-6-yl)- F-10 LC-MS: (ES, m/z):398.9. 1H-pyrazol-3-yl]methanol D-31[1-(2-Bromophenyl)-5-(1-methyl-1H-indazol-6- F-11 LC-MS: (ES, m/z): 383.yl)-1H-pyrazol-3-yl]methanol D-32[1-(2-Bromophenyl)-5-[3-(2,2-dimethylpropoxy)- F-12 LC-MS: (ES, m/z):417.00. phenyl]-1H-pyrazol-3-yl]methanol D-33[1-(2-Bromophenyl)-5-(3,5-dimethoxyphenyl)- F-13 LC-MS: (ES, m/z): 389.1H-pyrazol-3-yl]methanol D-34[1-(2-bromophenyl)-5-(1-propyl-1H-indazol-6- F-14 LC-MS: (ES, m/z):413.0. yl)-1H-pyrazol-3-yl]methanol D-35[1-(2-bromophenyl)-5-(3-cyclobutoxyphenyl)- F-15 LC-MS: (ES, m/z):399.2. 1H-pyrazol-3-yl]methanol D-36[1-(2-Fluorophenyl)-5-[3-(oxetan-3-ylmethoxy)- F-16 LC-MS: (ES, m/z):355.2. phenyl]-1H-pyrazol-3-yl]methanol D-37[5-(3-Cyclobutoxyphenyl)-1-(2-fluorophenyl)- F-17 LC-MS: (ES, m/z): 339.1H-pyrazol-3-yl]methanol D-38 [1-(2-Fluorophenyl)-5-[3-(oxetan-3-yloxy)-F-18 LC-MS: (ES, m/z): 341. phenyl]-1H-pyrazol-3-yl]methanol D-39[1-(2-Fluorophenyl)-5-[3-(2-methylpropoxy)- F-19 LC-MS: (ES, m/z): 341.phenyl]-1H-pyrazol-3-yl]methanol D-40[5-(3-cyclobutoxyphenyl)-1-(2-methylphenyl)- F-20 LC-MS: (ES, m/z): 334.1H-pyrazol-3-yl]methanol D-41[5-(3,5-Diethoxyphenyl)-1-(2-methylphenyl)-1H- F-21 LC-MS: (ES, m/z):353.00. pyrazol-3-yl]methanol D-42[5-(1-Ethyl-1H-indazol-6-yl)-1-(2-nitrophenyl)- F-22 LC-MS: (ES, m/z):364.3. 1H-pyrazol-3-yl]methanol D-43[5-[3-(2,2-dimethylpropoxy)phenyl]-1-(quinolin- F-23 LC-MS: (ES, m/z):8-yl)-1H-pyrazol-3-yl]methanol [M + 1] = 388. D-44[5-(3,5-Dimethoxyphenyl)-1-(2-ethoxyphenyl)- F-24 LC-MS: (ES, m/z): 355.1H-pyrazol-3-yl]methanol D-45[5-(1-Ethyl-1H-indazol-6-yl)-1-(1-methyl-1H- F-25 LC-MS: (ES, m/z): 372.indazol-7-yl)-1H-pyrazol-3-yl]methanol D-46[5-(3-Cyclobutoxyphenyl)-1-(1-methyl-1H- F-26 LC-MS: (ES, m/z): 375.indazol-7-yl)-1H-pyrazol-3-yl]methanol D-47[5-[3-(2,2-dimethylpropoxy)phenyl]-1-(1-methyl- F-27 LC-MS: (ES, m/z):391.10. 1H-indazol-7-yl)-1H-pyrazol-3-yl]methanol D-48[5-[3-(Cyclobutylmethoxy)phenyl]-1-(1-methyl- F-28 LC-MS: (ES, m/z):389. 1H-indazol-7-yl)-1H-pyrazol-3-yl]methanol D-49[5-[3-(Cyclopropylmethoxy)phenyl]-1-(1-methyl- F-29 LC-MS: (ES, m/z):375. 1H-indazol-7-yl)-1H-pyrazol-3-yl]methanol D-50[1-(1-Methyl-1H-indazol-7-yl)-5-[3-(2- F-30 LC-MS: (ES, m/z): 377.methylpropoxy)phenyl]-1H-pyrazol-3-yl]- methanol D-51[5-(3,5-dimethoxyphenyl)-1-(1-methyl-1H- F-31 LC-MS: (ES, m/z): 365.indazol-7-yl)-1H-pyrazol-3-yl]methanol D-52[5-(3,5-Diethoxyphenyl)-1-(1-methyl-1H- F-32 LC-MS: (ES, m/z): 393.05.indazol-7-yl)-1H-pyrazol-3-yl]methanol D-53[5-[3-(2,2-Dimethylpropoxy)phenyl]-1-(1-ethyl- F-33 LC-MS: (ES, m/z):404. 1H-indazol-7-yl)-1H-pyrazol-3-yl]methanol D-54[5-(3-Methoxyphenyl)-1-[2-(propan-2-yloxy)- F-34 LC-MS: (ES, m/z): 339.phenyl]-1H-pyrazol-3-yl]methanol D-55[1-(1,3-dimethyl-1H-indazol-7-yl)-5-[3-(2,2- F-35 LC-MS: (ES, m/z):405.35. dimethylpropoxy)phenyl]-1H-pyrazol-3- yl]methanol D-56[5-[3-(2,2-dimethylpropoxy)phenyl]-1-(1-methyl- F-361H-1,2,3-benzotriazol-7-yl)-1H-pyrazol-3- yl]methanol D-66[1-(2-chlorophenyl)-5-[3-(oxetan-3-yl- F-37 LC-MS: (ES, m/z): 371.0.methoxy)phenyl]-1H-pyrazol-3-yl]methanol D-67[1-(2-chlorophenyl)-5-(pyridin-2-yl)-1H-pyrazol- F-38 LC-MS: (ES, m/z):285.85. 3-yl]methanol D-68 [1-(2-Chlorophenyl)-5-(1-methyl-1H-indazol-6-F-39 LC-MS: (ES, m/z): 339. yl)-1H-pyrazol-3-yl]methanol D-69[1-(2-chlorophenyl)-5-(1-ethyl-1H-indazol-6-yl)- F-40 LC-MS: (ES, m/z):353. 1H-pyrazol-3-yl]methanol D-70[1-(2-Chlorophenyl)-5-(3-cyclobutoxyphenyl)- F-41 LC-MS: (ES, m/z): 355.1H-pyrazol-3-yl]methanol D-71 [1-(2-Chlorophenyl)-5-[3-(oxetan-3-yloxy)-F-42 LC-MS: (ES, m/z): 357. phenyl]-1H-pyrazol-3-yl]methanol D-72[1-(2-chlorophenyl)-5-(3-cyclopropoxyphenyl)- F-43 LC-MS: (ES, m/z):369.25. 1H-pyrazol-3-yl]methanol D-73[1-(2-Chlorophenyl)-5-[3-(2,2-dimethylpropoxy)- F-44 LC-MS: (ES, m/z):371.00. phenyl]-1H-pyrazol-3-yl]methanol D-74[1-(2-Chlorophenyl)-5-[3-(cyclobutylmeth- F-45 LC-MS: (ES, m/z): 368.95.oxy)phenyl]-1H-pyrazol-3-yl]methanol D-76[1-(2-Chlorophenyl)-5-(3,5-dimethoxyphenyl)- F-46 LC-MS: (ES, m/z): 345.1H-pyrazol-3-yl]methanol D-77[1-(2-Chlorophenyl)-5-(3,5-diethoxyphenyl)-1H- F-47 LC-MS: (ES, m/z):373.1. pyrazol-3-yl]methanol D-79[5-(3-cyclopropoxyphenyl)-1-(2-fluorophenyl)- F-48 LC-MS: (ES, m/z):325.25. 1H-pyrazol-3-yl]methanol D-80[1-(2-Bromophenyl)-5-(3-cyclopropoxyphenyl)- F-49 LC-MS: (ES, m/z): 387.1H-pyrazol-3-yl]methanol D-81[1-(2-Bromo-4-fluorophenyl)-5-(3-cyclopropoxy- F-50 LC-MS: (ES, m/z):405.0. phenyl)-1H-pyrazol-3-yl]methanol D-82[5-(3-Cyclopropoxyphenyl)-1-(2,4-dichloro- F-51 LC-MS: (ES, m/z):375.00. phenyl)-1H-pyrazol-3-yl]methanol D-83[5-(3-Cyclopropoxyphenyl)-1-(2,5-dichloro- F-52 LC-MS: (ES, m/z):375.05. phenyl)-1H-pyrazol-3-yl]methanol D-84[5-(3-Cyclopropoxyphenyl)-1-[2-(difluoro- F-53 LC-MS: (ES, m/z): 373.methoxy)phenyl]-1H-pyrazol-3-yl]methanol D-85[5-(3-Cyclopropoxyphenyl)-1-(2-ethoxyphenyl)- F-54 LC-MS: (ES, m/z):350. 1H-pyrazol-3-yl]methanol D-86[5-(3-Cyclopropoxyphenyl)-1-(2-methoxy- F-55 LC-MS: (ES, m/z): 337.phenyl)-1H-pyrazol-3-yl]methanol D-87[5-(3-Cyclopropoxyphenyl)-1-(2-methylphenyl)- F-56 LC-MS: (ES, m/z):321. 1H-pyrazol-3-yl]methanol D-88[5-(3-Cyclopropoxyphenyl)-1-(2-nitrophenyl)- F-57 LC-MS: (ES, m/z): 352.1H-pyrazol-3-yl]methanol D-89[5-(3-Cyclopropoxyphenyl)-1-[2-(propan-2-yl)- F-58 LC-MS: (ES, m/z):349. phenyl]-1H-pyrazol-3-yl]methanol D-90[5-(3-Cyclopropoxyphenyl)-1-[2-(trifluoro- F-59 LC-MS: (ES, m/z): 375.methyl)phenyl]-1H-pyrazol-3-yl]methanol D-91[5-(3-cyclopropoxyphenyl)-1-(1-methyl-1H- F-60 LC-MS: (ES, m/z): 361.indazol-7-yl)-1H-pyrazol-3-yl]methanol D-92[5-(3-Cyclopropoxyphenyl)-1-(1-methyl-1H- F-61 LC-MS: (ES, m/z): 361.indazol-4-yl)-1H-pyrazol-3-yl]methanol D-93[5-(3-Cyclopropoxyphenyl)-1-(1-ethyl-1H- F-62 LC-MS: (ES, m/z): 375.indazol-7-yl)-1H-pyrazol-3-yl]methanol D-97[5-(3-Cyclopropoxyphenyl)-1-(1-methyl-1H-1,3- F-63 LC-MS: (ES, m/z):361.2. benzodiazol-7-yl)-1H-pyrazol-3-yl]methanol D-99[1-[(2-Cyclopropoxyphenyl)methyl]-5-(3- F-64 LC-MS: (ES, m/z): 351.methoxyphenyl)-1H-pyrazol-3-yl]methanol D-100[1-[(2-chlorophenyl)methyl]-5-(3,5-dimethoxy- F-65 LC-MS: (ES, m/z):359. phenyl)-1H-pyrazol-3-yl]methanol D-107[5-(1-Benzothiophen-2-yl)-1-[(2-chlorophenyl)- F-66 LC-MS: (ES, m/z):354. methyl]-1H-pyrazol-3-yl]methanol D-110[1-[(2-chlorophenyl)methyl]-5-(1-methyl-1H- F-67 LC-MS: (ES, m/z): 353.indazol-6-yl)-1H-pyrazol-3-yl]methanol D-113[5-(3-Chloro-5-methoxyphenyl)-1-[(2- F-68 LC-MS: (ES, m/z): 373.ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methanol D-116[1-[(2-Chlorophenyl)methyl]-5-(1-methyl-1H- F-69 LC-MS: (ES, m/z): 353.indazol-4-yl)-1H-pyrazol-3-yl]methanol D-115[1-[(2-Ethoxyphenyl)methyl]-5-(1-ethyl-1H- F-70 LC-MS: (ES, m/z): 377.indazol-6-yl)-1H-pyrazol-3-yl]methanol D-121[5-(3-Ethoxyphenyl)-1-[(2-ethoxyphenyl)- F-71 LC-MS: (ES, m/z): 352.methyl]-1H-pyrazol-3-yl]methanol D-130[5-(3-Ethoxy-5-methoxyphenyl)-1-[(2- F-72 LC-MS: (ES, m/z): 383.ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methanol D-101[5-(3-Cyclopropoxyphenyl)-1-[(2-ethoxyphenyl)- F-73 LC-MS: (ES, m/z):364. methyl]-1H-pyrazol-3-yl]methanol D-102[5-(3-cyclopropoxyphenyl)-1-[(2-nitrophenyl)- F-74 LC-MS: (ES, m/z):366. methyl]-1H-pyrazol-3-yl]methanol D-103[1-[(2-Bromophenyl)methyl]-5-(3-cyclopropoxy- F-75 LC-MS: (ES, m/z):399. phenyl)-1H-pyrazol-3-yl]methanol D-104[1-[(2-chlorophenyl)methyl]-5-(2,3-dihydro-1,4- F-76 LC-MS: (ES, m/z):357. benzodioxin-6-yl)-1H-pyrazol-3-yl]methanol D-105[5-(2H-1,3-benzodioxol-5-yl)-1-[(2-chloro- F-77 LC-MS: (ES, m/z): 343.phenyl)methyl]-1H-pyrazol-3-yl]methanol D-106[1-[(2-Chlorophenyl)methyl]-5-(1-methyl-1H- F-78 LC-MS: (ES, m/z): 303.pyrazol-4-yl)-1H-pyrazol-3-yl]methanol D-108[1-[(2-chlorophenyl)methyl]-5-(1-methyl-1H- F-79 LC-MS: (ES, m/z): 351.indol-6-yl)-1H-pyrazol-3-yl]methanol D-109[1-[(2-Ethoxyphenyl)methyl]-5-(1-methyl-1H- F-80 LC-MS: (ES, m/z): 363.indazol-6-yl)-1H-pyrazol-3-yl]methanol D-128[5-(3,5-Diethoxyphenyl)-1-[(2-ethoxyphenyl)- F-81 LC-MS: (ES, m/z):397.05. methyl]-1H-pyrazol-3-yl]methanol D-111[1-[(2-Chlorophenyl)methyl]-5-(1-ethyl-1H- F-82 LC-MS: (ES, m/z): 367.indazol-6-yl)-1H-pyrazol-3-yl]methanol D-112[5-(1-Ethyl-1H-indazol-6-yl)-1-([pyridin-2- F-83 LC-MS: (ES, m/z): 334.yl]methyl)-1H-pyrazol-3-yl]methanol D-114[1-[(2-Chlorophenyl)methyl]-5-(1-methyl-1H- F-84 LC-MS: (ES, m/z): 352.indazol-5-yl)-1H-pyrazol-3-yl]methanol D-118[5-(3-Cyclobutoxyphenyl)-1-[(2-ethoxyphenyl)- F-85 LC-MS: (ES, m/z):379. methyl]-1H-pyrazol-3-yl]methanol D-119[1-[(2-Bromophenyl)methyl]-5-(3-cyclobutoxy- F-86 LC-MS: (ES, m/z): 412.phenyl)-1H-pyrazol-3-yl]methanol D-120[5-[3-(2,2-dimethylpropoxy)phenyl]-1-[(1- F-87 LC-MS: (ES, m/z): 405.3.methyl-1H-indazol-7-yl)methyl]-1H-pyrazol-3- yl]methanol D-123[5-[3-(2-methylpropoxy)phenyl]-1-([pyridin-2- F-88 LC-MS: (ES, m/z):338. yl]methyl)-1H-pyrazol-3-yl]methanol D-124[5-(3,5-Dimethoxyphenyl)-1-[(2-ethoxyphenyl)- F-89 LC-MS: (ES, m/z):369. methyl]-1H-pyrazol-3-yl]methanol D-125[5-(3,5-Dimethoxyphenyl)-1-(2-phenylethyl)-1H- F-90 LC-MS: (ES, m/z):339. pyrazol-3-yl]methanol D-126[5-(3,5-dimethoxyphenyl)-1-[(2-ethoxy-6- F-91 LC-MS: (ES, m/z): 387.1.fluorophenyl)methyl]-1H-pyrazol-3-yl]methanol D-127[5-(3,5-dimethoxyphenyl)-1-([pyridin-2- F-92 LC-MS: (ES, m/z): 326.yl]methyl)-1H-pyrazol-3-yl]methanol D-129[1-[(2-Chlorophenyl)methyl]-5-(3,5-diethoxy- F-93 LC-MS: (ES, m/z):387.00. phenyl)-1H-pyrazol-3-yl]methanol D-131[1-[(2-Chlorophenyl)methyl]-5-[2-(propan-2- F-94 LC-MS: (ES, m/z): 348.yloxy)-1,3-oxazol-5-yl]-1H-pyrazol-3- yl]methanol D-143[1-[(2-Chlorophenyl)methyl]-5-[3-(oxetan-3-yl- F-95 LC-MS: (ES, m/z):385.1. methoxy)phenyl]-1H-pyrazol-3-yl]methanol D-144[5-(3-Cyclopropoxyphenyl)-1-(1-[[2-(trimethyl- F-96 LC-MS: (ES, m/z):477. silyl)ethoxy]methyl]-1H-indazol-7-yl)-1H- pyrazol-3-yl]methanolD-145 [5-(3-Cyclopropoxyphenyl)-1-(1-[[2-(trimethyl- F-97 LC-MS: (ES,m/z): 477.2. silyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazol-3-yl]methanol D-146 [5-(3-Cyclopropoxyphenyl)-1-(3-methyl-1-[[2-F-98 LC-MS: (ES, m/z): 491.4.(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazol-3-yl]methanol Ester Product D-60[1-[(2-chlorophenyl)methyl]-5-(2-methoxyphenyl)- F-991H-pyrazol-3-yl]methanol D-61[5-(4-bromothien-2-yl)-1-[(2-chlorophenyl)- F-100methyl]-1H-pyrazol-3-yl]methanol D-62[1-[(2-chlorophenyl)methyl]-5-[5-(2- F-101methylpropoxy)thien-2-yl]-1H-pyrazol-3- yl]methanol D-631-[(2-chlorophenyl)-5-[2-(2-methylpropyl)-1,3- F-102oxazol-5-yl]-1H-pyrazol-3-yl]methanol D-64[1-[(2-chlorophenyl)methyl]-5-[2-(2-methyl- F-103propoxy)-1,3-thiazol-5-yl]-1H-pyrazol-3- yl]methanol D-75[1-(2-Chlorophenyl)-5-[3-(2-methyl- F-104propoxy)phenyl]-1H-pyrazol-3-yl]methanol D-78(5-Benzyl-1-[(2-chlorophenyl)methyl]-1H-pyrazol- F-105 3-yl)-methanolD-134 (5-(3-methoxyphenyl)-1-[[2-(propan-2-yloxy)- F-106phenyl]methyl]-1H-pyrazol-3-yl)-methanol D-135(5-(3-methoxyphenyl)-1-(2-methylpropyl)-1H- F-107 pyrazol-3-yl)methanolD-136 (5-(3-methoxyphenyl)-1-([oxan-4-yl]methyl)-1H- F-108pyrazol-3-yl)methanol D-138(1-[(2-chlorophenyl)methyl]-5-[3-[(propan-2-yl)- F-109carbamoyl]phenyl]-1H-pyrazol-3-yl)-methanol D-139(1-[(2,6-dimethoxyphenyl)methyl]-5-[3-(2-methyl- F-110propoxy)phenyl]-1H-pyrazol-3-yl)methanol D-141(1-[[4-(Dimethylamino)phenyl]methyl]-5-[3-(2- F-111methylpropoxy)phenyl]-1H-pyrazol-3-yl)methanol D-142(1-[[2-(dimethylamino)-6-fluorophenyl]methyl]-5- F-112(3-methoxyphenyl)-1H-pyrazol-3-yl)methanol D-147(1-[(2-chlorophenyl)methyl]-5-phenoxy-1H- F-113 pyrazol-3-yl)methanolD-1 (5-[[(tert-Butoxy)carbonyl](phenyl)amino]-1-[(2- F-114chlorophenyl)methyl]-1H-pyrazol-3-yl)methanol D-140(1-[(3-chloropyridin-2-yl)methyl]-5-(3-methoxy- F-115phenyl)-1H-pyrazol-3-yl)methanol

Intermediate F-116:[5-(3-Cyclopropoxyphenyl)-1-[[2-(dimethylamino)phenyl]methyl]-1H-pyrazol-3-yl]methanol

[1-[(2-Aminophenyl)methyl]-5-(3-cyclopropoxyphenyl)-1H-pyrazol-3-yl]-methanol

In a 25-mL flask were combined Int. F-74[5-(3-cyclopropoxyphenyl)-1-[(2-nitro-phenyl)methyl]-1H-pyrazol-3-yl]methanol(350 mg, 0.96 mmol, 1.00 equiv), AcOH (7.5 mL), H₂O (2.5 mL), and Zn(350 mg, 5.38 mmol, 5.60 equiv). The resulting mixture was stirred for 3h at rt. The solids were removed. The resulting solution was extractedwith 3×30 mL of EtOAc. The combined organic layers were dried overNa₂SO₄ and concentrated under vacuum to afford 300 mg (93%) of the titlecompound as a yellow oil. LC-MS (ES, m/z): 336.

[5-(3-Cyclopropoxyphenyl)-1-[[2-(dimethylamino)phenyl]methyl]-1H-pyrazol-3-yl]methanol

Into a 15-mL flask were combined the product from the previous step (300mg, 0.89 mmol, 1.00 equiv) MeOH (5 mL), AcOH (0.25 mL), HCHO (358 mg,11.92 mmol, 4.00 equiv), and NaCNBH₃ (225 mg, 3.57 mmol, 4.00 equiv).The resulting solution was stirred for 2 h at 40° C., quenched by theaddition of 5 mL of water/ice, and extracted with 3×30 mL of EtOAc. Thecombined organic layers were dried over Na₂SO₄, concentrated undervacuum, and purified by prep-TLC with EtOAc/hexane (1/1) to afford 300mg (92%) of the title compound as a yellow oil. LC-MS: (ES, m/z): 365.¹H NMR: (300 MHz, DMSO) δ 7.30 (dd, J=8.8, 7.6 Hz, 1H), 7.22 (td, J=7.6,7.2, 1.6 Hz, 1H), 7.14 (dd, J=8.1, 1.4 Hz, 1H), 7.00 (m, 2H), 6.88 (dd,J=6.9, 1.5 Hz, 2H), 6.73 (dd, J=7.7, 1.5 Hz, 1H), 6.42 (s, 1H), 5.35 (s,2H), 4.46 (s, 2H), 3.67 (dt, J=5.9, 3.1, 3.1 Hz, 1H), 2.55 (s, 6H), 0.62(ddd, J=5.9, 3.5, 1.3 Hz, 2H), 0.57 (m, 2H).

The following compounds were obtained via a similar zincreduction/alkylation sequence.

TABLE 13 Zn reduction/alkylation of (nitroaryl) pyrazoles Nitro CpdProduct Spectral F-22 [1-[2-(Dimethylamino)phenyl]-5-(1- F-117 LC-MS:(ES, m/z): 362.40. ethyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methanol F-57[5-(3-cyclopropoxyphenyl)-1-[2- F-118 LC-MS: (ES, m/z): 350.(dimethylamino)phenyl]-1H-pyrazol-3- yl]methanol

Intermediate G-1:3-(Bromomethyl)-1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazole

To a solution of Int. F-8 (4.3 g, 13.08 mmol, 1.00 equiv) in CH₂Cl₂ (100mL) was added CBr₄ (6.5 g, 1.50 equiv). This was followed by theaddition of a solution of PPh3 (7 g, 26.69 mmol, 2.00 equiv) in CH₂Cl₂(10 mL) dropwise with stirring at 0° C. in 5 min. The resulting solutionwas stirred for 4 h at rt. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:5). This resulted in the title compound as ayellow oil (3.5 g, 68%).

The following substituted 3-(bromomethyl)pyrazoles were obtained fromreaction of the corresponding (hydroxymethyl)pyrazole with PPh₃/CBr₄:

TABLE 14 CBr4 bromination of (hydroxymethyl) pyrazoles. Alcohol Bromocpd Spectral F-6 3-(Bromomethyl)-1-[(2-chloro- G-2 LC-MS: (ES, m/z) 435.phenyl)methyl]-5-[1,3-dimethyl- 1H-thieno[2,3-c]pyrazol-5-yl]-1H-pyrazole F-9 3-(bromomethyl)-5-[3-(2-methyl- G-3 LC-MS: (ES, m/z): 385.propoxy)phenyl]-1-phenyl-1H- pyrazole F-106-[3-(bromomethyl)-1-(2-bromo- G-4 LC-MS: (ES, m/z): 459.phenyl)-1H-pyrazol-5-yl]-1-ethyl- 1H-indazole F-146-[3-(bromomethyl)-1-(2-bromo- G-5 LC-MS: (ES, m/z): 475.2.phenyl)-1H-pyrazol-5-yl]-1-propyl- 1H-indazole F-193-(Bromomethyl)-1-(2- G-6 LC-MS: (ES, m/z): 403. fluorophenyl)-5-[3-(2-methylpropoxy)phenyl]-1H- pyrazole F-27 7-[3-(bromomethyl)-5-[3-(2,2-G-7 LC-MS: (ES, m/z): 453. dimethylpropoxy)phenyl]-1H-pyrazol-1-yl]-1-methyl-1H-indazole F-30 7-[3-(bromomethyl)-5-[3-(2- G-8LC-MS: (ES, m/z): 441.3. methylpropoxy)phenyl]-1H-pyrazol-1-yl]-1-methyl-1H-indazole F-34 3-(Bromomethyl)-5-(3- G-9 LC-MS:(ES, m/z): 401. methoxyphenyl)-1-[2-(propan-2- yloxy)phenyl]-1H-pyrazoleF-43 3-(bromomethyl)-1-(2-chloro- G-10 LC-MS: (ES, m/z): 405.15.phenyl)-5-(3-cyclopropoxyphenyl)- 1H-pyrazole F-46 3-(bromomethyl)-1-(2-G-11 LC-MS: (ES, m/z): 406. chlorophenyl)-5-(3,5- ¹H-NMR: (300 MHz,DMSO- dimethoxyphenyl)-1H-pyrazole d₆) δ 7.63 (dt, J = 7.5, 2.0 Hz, 2H),7.59-7.41 (m, 2H), 6.87 (s, 1H), 6.44 (t, J = 2.3 Hz, 1H), 6.34 (d, J =2.3 Hz, 2H), 4.70 (s, 2H), 3.61(s, 6H). F-49 3-(Bromomethyl)-1-(2-bromo-G-12 LC-MS: (ES, m/z): 447. phenyl)-5-(3-cyclopropoxyphenyl)- ¹H NMR(300 MHz, DMSO- 1H-pyrazole d6) δ 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.50(dddd, J = 29.7, 15.0, 7.5, 1.9 Hz, 3H), 7.23 (t, J = 8.0 Hz, 1H),6.97-6.85 (m, 2H), 6.85-6.75 (m, 2H), 4.78 (s, 1H), 4.68 (s, 1H), 3.55(tt, J = 6.0, 3.0 Hz, 1H), 0.69-0.58 (m, 2H), 0.49 (q, J = 2.7, 2.2 Hz,2H). F-55 3-(Bromomethyl)-5-(3- G-13 LC-MS: (ES, m/z): 399cyclopropoxyphenyl)-1-(2- methoxyphenyl)-1H-pyrazole F-607-[3-(bromomethyl)-5-(3- G-14 LC-MS: (ES, m/z): 425.cyclopropoxyphenyl)-1H-pyrazol- 1-yl]-1-methyl-1H-indazole F-643-(Bromomethyl)-1-[(2-cyclo- G-15 LC-MS: (ES, m/z): 414.propoxyphenyl)methyl]-5-(3- methoxyphenyl)-1H-pyrazole F-653-(Bromomethyl)-1-[(2- G-16 LC-MS: (ES, m/z): 423.chlorophenyl)methyl]-5-(3,5- ¹H-NMR: (CDCl3, ppm): δ:dimethoxyphenyl)-1H-pyrazole 7.42-7.30 (m, 2H), 7.29- 7.16 (m, 4H),6.83-6.71 (m, 2H), 6.52-6.36 (m, 8H), 5.45 (d, J = 1.0 Hz, 4H), 5.31 (s,1H), 4.57 (s, 4H), 3.66 (s, 12H). F-67 6-[3-(Bromomethyl)-1-[(2- G-17LC-MS: (ES, m/z): 417. chlorophenyl)methyl]-1H-pyrazol- ¹H NMR: (300MHz, CDCl₃) δ 5-yl]-1-methyl-1H-indazole 8.01 (d, J = 1.0 Hz, 1H), 7.74(dd, J = 8.3, 0.8 Hz, 1H), 7.42- 7.33 (m, 1H), 7.28 (s, 1H), 7.26 (dd, J= 3.8, 1.5 Hz, 2H), 7.10 (dd, J = 8.4, 1.4 Hz, 1H), 6.95-6.84 (m, 1H),6.58 (s, 1H), 5.48 (d, J = 0.8 Hz, 2H), 4.61 (s, 2H), 3.99 (s, 3H). F-826-[3-(bromomethyl)-1-[(2- G-18 LC-MS: (ES, m/z): 431.chlorophenyl)methyl]-1H-pyrazol- 5-yl]-1-ethyl-1H-indazole F-893-(Bromomethyl)-5-(3,5- G-19 LC-MS: (ES, m/z): 431.0.dimethoxyphenyl)-1-[(2- ethoxyphenyl)methyl]-1H-pyrazole F-945-[3-(Bromomethyl)-1-[(2-chloro- G-20 LC-MS: (ES, m/z): 411.phenyl)methyl]-1H-pyrazol-5-yl]-2- (propan-2-yloxy)-1,3-oxazole F-1182-[3-(Bromomethyl)-5-(3-cyclo- G-21 LC-MS: (ES, m/z): 413.propoxyphenyl)-1H-pyrazol-1-yl]- N,N-dimethylaniline Alcohol Bromo cpdF-99 3-(Bromomethyl)-1-[(2-chlorophenyl)methyl]-5-(2- G-22methoxyphenyl)-1H-pyrazole F-1003-(bromomethyl)-5-(4-bromothien-2-yl)-[1-[(2-chloro- G-23phenyl)methyl]-1H-pyrazole F-1063-(Bromomethyl)-(5-(3-methoxyphenyl)-1-[[2-(propan- G-242-yloxy)phenyl]methyl]-1H-pyrazole F-1073-(Bromomethyl)-(5-(3-methoxyphenyl)-1-(2-methyl- G-25propyl)-1H-pyrazole F-1083-(Bromomethyl)-(5-(3-methoxyphenyl)-1-([oxan-4-yl]- G-26methyl)-1H-pyrazole F-1162-([3-(Bromomethyl)-5-(3-cyclopropoxyphenyl)-1H- G-27pyrazol-1-yl]methyl)-N,N-dimethylaniline

Intermediate H-1: Methyl2-([1-[(3-chlorophenyl)methyl]-5-phenyl-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of Int. F-1 (0.288 g, 0.964 mmol) DMF was added NaH (60%)(0.077 g, 1.93 mmol) portionwise under N₂ at room temperature, andstirring was continued for 30 min. The mixture was cooled to 0° C. andmethyl 2-bromo-2-methyl-propanoate (0.16 mL, 1.25 mmol) was addeddropwise followed by NaI (0.143 g, 0.964 mmol). The reaction mixture waswarmed to room temperature gradually and stirred overnight. At the endof this period aq. NH₄Cl solution was added, and the mixture waspartitioned with EtOAc (40 mL). The aqueous layer was extracted withEtOAc (2×20 mL). The combined EtOAc layers were washed with brine anddried over Na₂SO₄, and the solvent was evaporated. The residue waschromatographed over SiO₂ (ISCO CombiFlash® Rf 200) using 0-50% gradientof EtOAc in hexanes to afford the title product as an oil (0.068 g,38%). ¹H NMR (CDCl₃, 400 MHz): δ 1.56 (s, 6H). 3.68 (s, 3H), 4.58 (s,2H), 5.25 (s, 2H), 6.45 (s, 1H), 6.87-6.93 (m, 1H), 7.00 (s, 1H),7.16-7.22 (m, 2H), 7.26-7.34 (m, 2H), 7.34-7.42 (m, 3H).

The following substituted pyrazole carboxylic esters were obtained fromWilliamson ether synthesis of the corresponding (hydroxymethyl)pyrazolewith BrC(CH₃)₂COOMe:

TABLE 15 Ether synthesis from (hydroxymethyl) pyrazoles. Alcohol ProductSpectral F-10 Methyl 2-([1-(2-bromo- H-2 LC-MS: (ES, m/z): 499.1.phenyl)-5-(1-ethyl-1H- ¹H NMR: (300 MHz, DMSO) δ 8.01 (d,indazol-6-yl)-1H- J = 1.0 Hz, 1H), 7.74 (dd, J = 8.0, 1.5pyrazol-3-yl]methoxy)-2- Hz, 1H), 7.66 (dd, J = 8.4, 0.8 Hz, 1H),methylpropanoate 7.62 (dd, J = 7.8, 1.8 Hz, 1H), 7.53 (td, J = 7.7, 7.6,1.5 Hz, 1H), 7.48 (dd, J = 1.5, 0.8 Hz, 1H), 7.44 (m, 1H), 6.96 (dd, J =8.4, 1.4 Hz, 1H), 6.79 (s, 1H), 4.50 (s, 2H), 4.32 (q, J = 7.2, 7.2, 7.2Hz, 2H), 3.72 (s, 3H), 1.47 (s, 6H), 1.24 (t, J = 7.2, 7.2 Hz, 3H). F-11Methyl 2-([1-(2-bromo- H-3 LC-MS: (ES, m/z): 483.phenyl)-5-(1-methyl-1H- ¹H NMR: (300 MHz, DMSO-d₆) δ 7.99indazol-6-yl)-1H- (d, J = 1.0 Hz, 1H), 7.73 (dd, J = 7.9,pyrazol-3-yl]methoxy)-2- 1.5 Hz, 1H), 7.67-7.47 (m, 4H), 7.42methylpropanoate (td, J = 7.6, 1.9 Hz, 1H), 6.86 (dd, J = 8.4, 1.4 Hz,1H), 6.78 (s, 1H), 4.49 (s, 2H), 3.94 (s, 3H), 3.71 (s, 3H), 1.46 (s,6H). F-12 Methyl 2-([1-(2-bromo- H-4 LC-MS: (ES, m/z): 517.05.phenyl)-5-[3-(2,2- ¹H NMR (300 MHz, DMSO) δ 7.76 (dd, dimethyl- J = 7.7,1.3 Hz, 1H), 7.53 (m, 2H), 7.44 propoxy)phenyl]-1H- (ddd, J = 7.8, 6.6,2.6 Hz, 1H), 7.18 (t, pyrazol-3-yl]methoxy)-2- J = 8.0, 8.0 Hz, 1H),6.81 (m, 2H), 6.70 methylpropanoate (d, J = 2.4 Hz, 2H), 4.45 (s, 2H),3.70 (s, 3H), 3.39 (s, 2H), 1.45 (s, 6H), 0.93 (s, 9H). F-20 Methyl2-([5-(3-cyclo- H-5 LC-MS: (ES, m/z): 434. butoxyphenyl)-1-(2- ¹H NMR:(300 MHz, DMSO-d₆) δ methylphenyl)-1H- 12.68 (s, 1H), 7.38-7.20 (m, 2H),7.05- pyrazol-3-yl]methoxy)-2- 6.94 (m, 2H), 6.92-6.82 (m, 2H),methylpropanoate 6.75-6.62 (m, 2H), 6.42 (s, 1H), 5.26 (s, 2H), 4.50 (q,J = 7.1 Hz, 1H), 4.42 (s, 2H), 4.02 (q, J = 6.9 Hz, 2H), 2.30- 2.15 (m,2H), 2.03-1.86 (m, 2H), 1.79- 1.65 (m, 1H), 1.63-1.47 (m, 1H), 1.40 (s,6H), 1.24 (t, J = 6.9 Hz, 3H). F-25 Methyl 2-([5-(1-ethyl- H-6 LC-MS:(ES, m/z): 472. 1H-indazol-6-yl)-1-(1- ¹H NMR: (400 MHz, DMSO-d₆) δ 8.18methyl-1H-indazol-7-yl)- (s, 1H), 7.97 (d, J = 0.9 Hz, 1H), 7.901H-pyrazol-3- (dd, J = 8.1, 1.0 Hz, 1H), 7.59 (dd, J = yl]methoxy)-2-8.4, 0.8 Hz, 1H), 7.54 (q, J = 1.1 Hz, methylpropanoate 1H), 7.46 (dd, J= 7.3, 1.0 Hz, 1H), 7.18 (dd, J = 8.1, 7.3 Hz, 1H), 6.95 (dd, J = 8.4,1.4 Hz, 1H), 6.91 (s, 1H), 4.55 (s, 2H), 4.26 (t, J = 7.2 Hz, 2H), 3.72(s, 3H), 3.48 (s, 3H), 1.48 (s, 6H), 1.17 (t, J = 7.1 Hz, 3H). F-26Methyl 2-([5-(3-cyclo- H-7 LC: (ES, m/z): 475. butoxyphenyl)-1-(1- ¹HNMR: (300 MHz, DMSO-d₆) δ 8.21 methyl-1H-indazol-7-yl)- (s, 1H), 7.93(dd, J = 8.1, 1.0 Hz, 1H), 1H-pyrazol-3-yl]- 7.38 (dd, J = 7.3, 1.0 Hz,1H), 7.28- methoxy)-2-methyl- 7.09 (m, 2H), 6.94-6.86 (m, 1H), 6.79propanoate (s, 1H), 6.75-6.66 (m, 1H), 6.45 (dd, J = 2.5, 1.6 Hz, 1H),4.50 (s, 2H), 4.19- 4.05 (m, 1H), 3.70 (s, 3H), 3.43 (s, 3H), 2.10-1.95(m, 2H), 1.89-1.74 (m, 2H), 1.67 (dd, J = 11.6, 8.3 Hz, 1H), 1.52 (d, J= 8.3 Hz, 2H), 1.45 (s, 6H). F-27 Methyl 2-([5-[3-(2,2- H-8 LC-MS: (ES,m/z): 491.3. dimethylpropoxy)- ¹H NMR: (300 MHz, DMSO) δ 8.19 (s,phenyl]-1-(1-methyl-1H- 1H), 7.92 (dd, J = 8.1, 1.0 Hz, 1H), 7.39indazol-7-yl)-1H- (dd, J = 7.3, 1.0 Hz, 1H), 7.16 (m, 2H),pyrazol-3-yl]methoxy)-2- 6.81 (m, 3H), 6.62 (m, 1H), 4.51 (s,methylpropanoate 2H), 3.70 (s, 3H), 3.42 (s, 3H), 3.17 (d, J = 6.6 Hz,2H), 1.46 (s, 6H), 0.87 (s, 9H). F-28 Methyl 2-([5-[3-(cyclo- H-9 LC-MS:(ES, m/z): 489. butylmethoxy)phenyl]-1- ¹H NMR: (300 MHz, DMSO-d₆) δ8.19 (1-methyl-1H-indazol-7- (s, 1H), 7.92 (dd, J = 8.1, 1.0 Hz, 1H),yl)-1H-pyrazol-3-yl]- 7.39 (dd, J = 7.3, 1.0 Hz, 1H), 7.28-methoxy)-2-methyl- 7.02 (m, 2H), 6.94-6.71 (m, 3H), 6.65 propanoate (dd,J = 2.6, 1.6 Hz, 1H), 4.50 (s, 2H), 3.70 (s, 3H), 3.56 (d, J = 6.8 Hz,2H), 3.43 (s, 3H), 3.16 (s, 1H), 2.04-1.91 (m, 2H), 1.89-1.77 (m, 2H),1.66 (dt, J = 11.0, 7.6 Hz, 2H), 1.45 (s, 6H). F-30 Methyl2-methyl-2-([1- H-10 LC-MS: (ES, m/z): 477. (1-methyl-1H-indazol-7- ¹HNMR (400 MHz, DMSO-d₆): δ 8.20 yl)-5-[3-(2-methyl- (s, 1H), 7.92 (dd, J= 8.1, 1.0 Hz, 1H), propoxy)phenyl]-1H- 7.40 (dd, J = 7.4, 1.0 Hz, 1H),7.26- pyrazol-3-yl]methoxy]- 7.08 (m, 2H), 6.91-6.74 (m, 3H), 6.64propanoate (dd, J = 2.5, 1.5 Hz, 1H), 4.52 (s, 2H), 3.71 (s, 3H), 3.44(s, 3H), 3.35 (d, J = 6.6 Hz, 2H), 1.81 (dh, J = 13.4, 6.8 Hz, 1H), 1.47(s, 6H), 0.85 (d, J = 6.6 Hz, 6H). F-33 Methyl 2-([5-[3-(2,2-di- H-11LC-MS: (ES, m/z): 504. methylpropoxy)phenyl]- ¹H NMR (400 MHz, DMSO-d₆)δ 8.25 1-(1-ethyl-1H-indazol-7- (s, 1H), 7.93 (dd, J = 8.1, 1.0 Hz, 1H),yl)-1H-pyrazol-3-yl]- 7.33 (dd, J = 7.3, 1.0 Hz, 1H), 7.27-methoxy)-2-methyl- 7.07 (m, 2H), 6.87 (s, 1H), 6.84-6.72 propanoate (m,2H), 6.61 (dd, J = 2.5, 1.6 Hz, 1H), 4.52 (s, 2H), 3.71 (s, 2H), 3.18(s, 3H), 3.16 (s, 2H), 1.47 (s, 6H), 1.10 (t, J = 7.1 Hz, 3H), 0.87 (s,9H). F-47 Methyl 2-([1-(2-chloro- H-12 LC-MS: (ES, m/z): 473.05.phenyl)-5-(3,5-diethoxy- ¹H NMR: (300 MHz, DMSO) δ 7.57 (m,phenyl)-1H-pyrazol-3- 4H), 6.70 (s, 1H), 6.38 (t, J = 2.3, 2.3yl]methoxy)-2-methyl- Hz, 1H), 6.30 (d, J = 2.2 Hz, 2H), 4.45 propanoate(s, 2H), 3.85 (q, J = 7.0, 7.0, 7.0 Hz, 4H), 3.71 (s, 3H), 1.45 (s, 6H),1.22 (t, J = 7.0, 7.0 Hz, 6H). F-48 Methyl 2-([5-(3-cyclo- H-13 LC-MS:(ES, m/z): 425.2. propoxyphenyl)-1-(2- ¹H-NMR: δ_(H) (300 MHz, DMSO-D₆)fluorophenyl)-1H- 7.54 (2 H, m), 7.31 (3 H, m), 6.90 (3 H,pyrazol-3-yl]methoxy]- m), 6.67 (1 H, s), 4.45 (2 H, s), 3.69 (32-methylpropanoate H, s), 3.61 (1 H, dp, J = 6.1, 3.1, 3.1, 3.0, 3.0Hz), 1.44 (6 H, s), 0.54 (4 H, m). F-61 Methyl 2-([5-(3-cyclo- H-14LC-MS: (ES, m/z): 461. propoxyphenyl)-1-(1- ¹H NMR (300 MHz, DMSO-d₆) δ7.77- methyl-1H-indazol-4-yl)- 7.62 (m, 2H), 7.42 (dd, J = 8.6, 7.31H-pyrazol-3-yl]- Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.01-methoxy)-2-methyl- 6.84 (m, 4H), 6.72 (s, 1H), 4.52 (s, 2H), propanoate4.08 (s, 3H), 3.71 (s, 3H), 3.57 (tt, J = 6.2, 3.0 Hz, 1H), 1.48 (s,6H), 0.60- 0.46 (m, 2H), 0.40 (dq, J = 6.8, 3.4 Hz, 2H). F-62 Methyl2-([5-(3-cyclo- H-15 LC-MS: (ES, m/z): 475. propoxyphenyl)-1-(1- ¹H NMR(300 MHz, DMSO-d₆) δ 8.24 ethyl-1H-indazol-7-yl)- (s, 1H), 7.91 (dd, J =8.0, 1.0 Hz, 1H), 1H-pyrazol-3-yl]- 7.30 (dd, J = 7.3, 1.0 Hz, 1H),7.27- methoxy)-2-methyl- 7.05 (m, 2H), 6.93 (dt, J = 7.8, 1.2 Hz,propanoate 1H), 6.89-6.80 (m, 2H), 6.76 (dd, J = 2.5, 1.6 Hz, 1H), 4.51(s, 2H), 3.70 (s, 3H), 3.35 (d, J = 4.6 Hz, 2H), 3.33- 3.29 (m, 1H),1.45 (s, 6H), 1.10 (t, J = 7.1 Hz, 3H), 0.52-0.28 (m, 4H). F-66 Methyl2-([5-(1-benzo- H-16 LC-MS: (ES, m/z): 454. thiophen-2-yl)-1-[(2- ¹HNMR: (300 MHz, DMSO-d₆) δ 8.04- chlorophenyl)methyl]- 7.96 (m, 1H),7.90-7.82 (m, 1H), 1H-pyrazol-3- 7.59 (d, J = 0.8 Hz, 1H), 7.53-7.47 (m,yl]methoxy)-2- 1H), 7.46-7.39 (m, 2H), 7.32 (tt, J = methylpropanoate7.4, 5.5 Hz, 2H), 6.78-6.70 (m, 1H), 6.69 (s, 1H), 5.63 (s, 2H), 4.43(s, 2H), 3.71 (s, 3H), 1.44 (s, 6H). F-69 Methyl 2-([1-[(2-chloro- H-17LC-MS: (ES, m/z): 453. phenyl)methyl]-5-(1- ¹H NMR (300 MHz, DMSO-d₆) δ7.94 methyl-1H-indazol-4-yl)- (d, J = 1.0 Hz, 1H), 7.79-7.65 (m, 1H),1H-pyrazol-3-yl]- 7.45 (dd, J = 8.5, 7.1 Hz, 1H), 7.41-methoxy)-2-methyl- 7.32 (m, 1H), 7.29-7.21 (m, 2H), 7.10 propanoate (dd,J = 7.1, 0.8 Hz, 1H), 6.85-6.73 (m, 1H), 6.58 (s, 1H), 5.40 (s, 2H),4.45 (s, 2H), 4.09 (s, 3H), 3.69 (s, 3H), 1.44 (s, 6H). F-70 Methyl2-([1-[(2-ethoxy- H-18 LC-MS: (ES, m/z): 477. phenyl)methyl]-5-(1- ¹HNMR: (400 MHz, DMSO-d₆) δ 8.09 ethyl-1H-indazol-6-yl)- (d, J = 1.0 Hz,1H), 7.80 (dd, J = 8.3, 1H-pyrazol-3-yl]- 0.8 Hz, 1H), 7.68 (q, J = 1.0Hz, 1H), methoxy)-2-methyl- 7.27-7.19 (m, 1H), 7.16 (dd, J = 8.4,propanoate 1.4 Hz, 1H), 6.95 (dd, J = 8.2, 1.1 Hz, 1H), 6.86 (td, J =7.5, 1.1 Hz, 1H), 6.72 (dd, J = 7.5, 1.7 Hz, 1H), 6.51 (s, 1H), 5.33 (s,2H), 4.41 (s, 2H), 4.40-4.35 (m, 2H), 3.93 (d, J = 7.0 Hz, 2H), 3.70 (s,3H), 1.44 (s, 6H), 1.33 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 6.9 Hz, 3H).F-71 Methyl 2-([5-(3-ethoxy- H-19 LC-MS: (ES, m/z): 452.phenyl)-1-[(2-ethoxy- ¹H NMR (400 MHz, DMSO-d₆) δ 7.33phenyl)methyl]-1H- (t, J = 7.9 Hz, 1H), 7.24 (ddd, J = 8.2,pyrazol-3-yl]methoxy)-2- 7.3, 1.7 Hz, 1H), 7.04-6.91 (m, 3H),methylpropanoate 6.90-6.79 (m, 2H), 6.69 (dd, J = 7.6, 1.7 Hz, 1H), 6.43(s, 1H), 5.77 (s, 1H), 5.26 (s, 2H), 4.38 (s, 2H), 3.96 (dq, J = 26.5,6.9 Hz, 4H), 3.69 (s, 3H), 1.42 (s, 6H), 1.25 (dt, J = 18.7, 7.0 Hz,6H). F-75 Methyl 2-([1-[(2-bromo- H-20 LC-MS: (ES, m/z): 499.3.phenyl)methyl]-5-(3- ¹H NMR: (300 MHz, DMSO) δ 7.62 cyclopropoxyphenyl)-(dd, J = 7.9, 1.3 Hz, 1H), 7.35 (tdd, J = 1H-pyrazol-3-yl]- 7.5, 7.5,2.6, 1.0 Hz, 2H), 7.23 (td, J = methoxy)-2- 7.6, 7.6, 1.8 Hz, 1H), 7.01(m, 3H), 6.69 methylpropanoate (dd, J = 7.7, 1.7 Hz, 1H), 6.47 (s, 1H),5.34 (s, 2H), 4.40 (s, 2H), 3.68 (s, 4H), 1.42 (s, 6H), 0.59 (tt, J =5.8, 5.8, 2.4, 2.4 Hz, 4H). F-79 Methyl 2-([1-[(2-chloro- H-21 LC-MS:(ES, m/z): 451. phenyl)methyl]-5-(1- ¹H NMR (400 MHz, DMSO-d₆) δ 7.59methyl-1H-indol-6-yl)- (d, J = 8.1 Hz, 1H), 7.48-7.42 (m, 2H),1H-pyrazol-3-yl]- 7.41 (d, J = 3.1 Hz, 1H), 7.34-7.29 (m,methoxy)-2-methyl- 2H), 7.03 (dd, J = 8.2, 1.5 Hz, 1H), 6.84- propanoate6.76 (m, 1H), 6.49-6.42 (m, 2H), 5.44 (s, 2H), 4.42 (s, 2H), 3.74 (s,3H), 3.70 (s, 3H), 1.44 (s, 6H). F-80 Methyl 2-([1-[(2-ethoxy- H-22LC-MS: (ES, m/z): 463. phenyl)methyl]-5-(1- ¹H NMR: (400 MHz, DMSO-d₆) δ8.09 methyl-1H-indazol-6-yl)- (d, J = 0.9 Hz, 1H), 7.80 (dd, J = 8.3,1H-pyrazol-3-yl]- 0.8 Hz, 1H), 7.69 (q, J = 1.0 Hz, 1H),methoxy)-2-methyl- 7.28-7.20 (m, 1H), 7.16 (dd, J = 8.4, propanoate 1.4Hz, 1H), 6.95 (dd, J =8.4, 1.1 Hz, 1H), 6.86 (td, J = 7.5, 1.0 Hz, 1H),6.75 (dd, J = 7.5, 1.7 Hz, 1H), 6.49 (s, 1H), 5.32 (s, 2H), 4.41 (s,2H), 4.01 (s, 3H), 3.93 (q, J = 7.0 Hz, 2H), 3.70 (s, 3H), 1.43 (s, 6H),1.12 (t, J = 6.9 Hz, 3H). F-90 Methyl 2-([5-(3,5-di- H-23 LC-MS: (ES,m/z): 439. methoxyphenyl)-1-(2- ¹H NMR (400 MHz, DMSO-d₆) δ 7.29-phenylethyl)-1H-pyrazol- 7.11 (m, 3H), 7.04-6.94 (m, 2H),3-yl]methoxy)-2-methyl- 6.54 (t, J = 2.3 Hz, 1H), 6.37 (d, J = 2.3propanoate Hz, 2H), 6.26 (s, 1H), 4.39 (s, 2H), 4.25 (dd, J = 8.1, 6.6Hz, 2H), 3.74 (s, 6H), 3.70 (s, 3H), 3.05 (t, J = 7.3 Hz, 2H), 1.43 (s,6H). F-13 Methyl 2-([1-(2-bromophenyl)- H-24 LC-MS: (ES, m/z): 489.5-(3,5-dimethoxy-phenyl)- 1H-pyrazol-3-yl]methoxy)- 2-methylpropanoateF-14 Methyl 2-([1-(2-bromophenyl)- H-25 LC-MS: (ES, m/z): 535.1.5-(1-propyl-1H-indazol- 6-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate F-15 Methyl 2-([1-(2-bromophenyl)- H-26 LC-MS: (ES,m/z): 499.3. 5-(3-cyclobutoxy- phenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate F-16 Methyl 2-([1-(2-fluorophenyl)-5- H-27 LC-MS:(ES, m/z): 455.3. [3-(oxetan-3-yl-methoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate F-17 Methyl 2-([5-(3-cyclo-H-28 LC-MS: (ES, m/z): 439. butoxyphenyl)-1-(2-fluoro-phenyl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate F-18 Methyl2-([1-(2-fluorophenyl)-5- H-29 LC-MS: (ES, m/z): 440.[3-(oxetan-3-yloxy)-phenyl]-1H- pyrazol-3-yl]methoxy)-2-methyl-propanoate F-21 Methyl 2-([5-(3,5-diethoxy- H-30 LC-MS: (ES, m/z):453.25. phenyl)-1-(2-methylphenyl)-1H- pyrazol-3-yl]methoxy)-2-methylpropanoate F-24 Methyl 2-([5-(3,5-dimethoxy- H-31 LC-MS: (ES,m/z): 455. phenyl)-1-(2-ethoxyphenyl)-1H- pyrazol-3-yl]methoxy)-2-methylpropanoate F-29 Methyl 2-([5-[3-(cyclo- H-32 LC-MS: (ES, m/z):475. propylmethoxy)phenyl]-1-(1- methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate F-31 Methyl2-([5-(3,5-dimethoxy- H-33 LC-MS: (ES, m/z): 465.phenyl)-1-(1-methyl-1H- indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate F-32 Methyl 2-([5-(3,5-diethoxy- H-34LC-MS: (ES, m/z): 493.15. phenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3- yl]methoxy)-2-methyl- propanoate F-35 Methyl2-([1-(1,3-dimethyl- H-35 LC-MS: (ES, m/z): 505.3.1H-indazol-7-yl)-5-[3-(2,2- dimethylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-36 Methyl2-([5-[3-(2,2-dimethyl- H-36 LC-MS: (ES, m/z): 492propoxy)phenyl]-1-(1-methyl-1H-1,2,3- benzotriazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate F-37 Methyl 2-([1-(2-chlorophenyl)- H-37LC-MS: (ES, m/z): 471.3. 5-[3-(oxetan-3-yl-methoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-38 Methyl2-([1-(2-chlorophenyl)- H-38 LC-MS: (ES, m/z): 386.00.5-(pyridin-2-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoate F-39Methyl 2-([1-(2-chlorophenyl)-5- H-39 LC-MS: (ES, m/z): 455.(1-methyl-1H-indazol-6-yl)-1H- pyrazol-3-yl]methoxy)-2- methylpropanoateF-40 Methyl 2-([1-(2-chlorophenyl)- H-40 LC-MS: (ES, m/z): 453.5-(1-ethyl-1H-indazol-6-yl)-1H- pyrazol-3-yl]methoxy)-2-methylpropanoate F-41 Methyl 2-([1-(2-chlorophenyl)- H-41 LC-MS: (ES,m/z): 455. 5-(3-cyclo-butoxyphenyl)-1H- pyrazol-3-yl]methoxy)-2-methylpropanoate F-42 Methyl 2-([1-(2-chlorophenyl)- H-42 LC-MS: (ES,m/z): 457. 5-[3-(oxetan-3-yloxy)-phenyl]- 1H-pyrazol-3-yl]methoxy)-2-methylpropanoate F-44 Methyl 2-([1-(2-chlorophenyl)- H-43 LC-MS: (ES,m/z): 471.10. 5-[3-(2,2-dimethyl- propoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate F-45 methyl 2-([1-(2-chlorophenyl)-H-44 LC-MS: (ES, m/z): 469.15. 5-[3-(cyclobutyl-methoxy)phenyl]-1H-pyrazol- 3-yl]methoxy)-2-methyl- propanoate F-46Methyl 2-([1-(2-chlorophenyl)- H-45 LC-MS: (ES, m/z): 445.5-(3,5-dimethoxy-phenyl)-1H- pyrazol-3-yl]methoxy)-2- methylpropanoateF-49 Methyl 2-([1-(2-bromophenyl)- H-46 LC-MS: (ES, m/z): 486.955-(3-cycloprop-oxyphenyl)-1H- pyrazol-3-yl]methoxy)- 2-methyl-propanoateF-50 Methyl 2-([1-(2-bromo-4- H-47 LC-MS: (ES, m/z): 503.1.fluorophenyl)-5-(3-cyclo- propoxyphenyl)-1H-pyrazol- 3-yl]methoxy)-2-methylpropanoate F-51 Methyl 2-([5-(3-cyclo- H-48 LC-MS: (ES, m/z):475.05. propoxyphenyl)-1-(2,4-dichloro-phenyl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate F-52 Methyl2-([5-(3-cyclo- H-49 LC-MS: (ES, m/z): 475.1.propoxyphenyl)-1-(2,5-dichloro- phenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate F-53 Methyl 2-([5-(3-cyclo- H-50 LC-MS: (ES, m/z):473. propoxyphenyl)-1-[2-(difluoro- methoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate F-54 Methyl 2-([5-(3-cyclo- H-51 LC-MS:(ES, m/z): 450. propoxyphenyl)-1-(2-ethoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-56 Methyl 2-([5-(3-cyclo-H-52 LC-MS: (ES, m/z): 421. propoxyphenyl)-1-(2-methyl-phenyl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate F-58 Methyl2-([5-(3-cyclo- H-53 LC-MS: (ES, m/z): 449.propoxyphenyl)-1-[2-(propan-2- yl)phenyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropanoate F-59 Methyl 2-([5-(3-cyclopro- H-54 LC-MS: (ES, m/z):475. poxyphenyl)-1-[2-(trifluoro- methyl)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate F-60 Methyl 2-([5-(3-cyclo- H-55 LC-MS:(ES, m/z): 461. propoxyphenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3- yl]methoxy)-2-methyl- propanoate F-63 Methyl2-([5-(3-cyclo- H-56 LC-MS: (ES, m/z): 461.1.propoxyphenyl)-1-(1-methyl-1H- 1,3-benzodiazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-68 Methyl 2-([5-(3-chloro-5- H-57LC-MS: (ES, m/z): 473 methoxyphenyl)-1-[(2-ethoxy-phenyl)methyl]-1H-pyrazol-3- yl]methoxy)-2- methylpropanoate F-72 Methyl2-([5-(3-ethoxy-5- H-58 LC-MS: (ES, m/z): 483. methoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H- pyrazol-3-yl]methoxy)-2- methylpropanoate F-73Methyl 2-([5-(3-cyclo- H-59 LC-MS: (ES, m/z): 465. propoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H- pyrazol-3-yl]methoxy)-2- methylpropanoate F-76Methyl 2-([1-[(2-chloro- H-60 LC-MS: (ES, m/z): 457.phenyl)methyl]-5-(2,3-dihydro- 1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-77 Methyl 2-([5-(2H-1,3-benzo- H-61LC-MS: (ES, m/z): 443. dioxol-5-yl)-1-[(2-chloro-phenyl)methyl]-1H-pyrazol- 3-yl]methoxy)-2-methyl- propanoate F-78Methyl 2-([1-[(2-chloro- H-62 LC-MS: (ES, m/z): 403.phenyl)methyl]-5-(1-methyl-1H- pyrazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate F-81 Methyl 2-([5-(3,5-diethoxy- H-63LC-MS: (ES, m/z): 497.25. phenyl)-1-[(2-ethoxy-phenyl)methyl]-1H-pyrazol- 3-yl]methoxy)-2-methyl- propanoate F-82Methyl 2-([1-[(2-chloro- H-64 LC-MS: (ES, m/z): 467.phenyl)methyl]-5-(1-ethyl-1H- indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate F-83 Methyl 2-([5-(1-ethyl-1H- H-65LC-MS: (ES, m/z): 434. indazol-6-yl)-1-([pyridin-2-yl]methyl)-1H-pyrazol-3- yl]methoxy)-2- methylpropanoate F-84 Methyl2-([1-[(2-chloro- H-66 LC-MS: (ES, m/z): 452.phenyl)methyl]-5-(1-methyl-1H- indazol-5-yl)-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate F-85 Methyl 2-([5-(3-cyclo- H-67 LC-MS:(ES, m/z): 479. butoxyphenyl)-1-[(2-ethoxy- phenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-86 Methyl 2-([1-[(2-bromo- H-68 LC-MS:(ES, m/z): 512. phenyl)methyl]-5-(3-cyclo- butoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-87 Methyl 2-([5-[3-(2,2-dimethyl- H-69LC-MS: (ES, m/z): 505. propoxy)phenyl]-1-[(1-methyl-1H-indazol-7-yl)methyl]- 1H-pyrazol-3-yl]methoxy)-2-methylpropanoate F-88 Methyl 2-methyl-2-([5-[3-(2- H-70 LC-MS: (ES,m/z): 438. methylpropoxy)phenyl]-1- ([pyridin-2-yl]methyl)-1H-pyrazol-3-yl]methoxy)- propanoate F-89 Methyl 2-([5-(3,5-dimethoxy- H-71LC-MS: (ES, m/z): 469. phenyl)-1-[(2-ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-91 Methyl2-([5-(3,5-dimethoxy- H-72 LC-MS: (ES, m/z): 487.2.phenyl)-1-[(2-ethoxy-6- fluorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-92 Methyl2-([5-(3,5-dimethoxy- H-73 LC-MS: (ES, m/z): 426. phenyl)-1-([pyridin-2-yl]methyl)-1H-pyrazol-3- yl]methoxy)-2- methylpropanoate F-93 Methyl2-([1-[(2-chloro- H-74 LC-MS: (ES, m/z): 487.2.phenyl)methyl]-5-(3,5-diethoxy- phenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate F-95 Methyl 2-([1-[(2-chloro- H-75 LC-MS: (ES, m/z):485.2. phenyl)methyl]-5-[3-(oxetan-3- ylmethoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-96 Methyl 2-([5-(3-cyclo- H-76 LC-MS:(ES, m/z): 577. propoxyphenyl)-1-(1-[[2-(tri-methylsilyl)ethoxy]methyl]- 1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-97 Methyl 2-([5-(3-cyclo- H-77 LC-MS:(ES, m/z): 577.3. propoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]- 1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate F-98 Methyl 2-([5-(3-cyclo-H-78 LC-MS: (ES, m/z): 591.3. propoxyphenyl)-1-(3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]- 1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate F-4 Methyl 2-([5-(3-methoxy-H-79 LC-MS: (ES, m/z): 394. phenyl)-1-(2-methylphenyl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate F-2 Methyl2-([1-[(2-chloro- H-80 LC-MS: (ES, m/z): 453.phenyl)methyl]-5-(1-methyl-1H- 1,3-benzodiazol-6-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoate F-5 Methyl 2-([1-[(2-chloro-H-81 LC-MS: (ES, m/z): 468. phenyl)methyl]-5-(1-ethyl-1H-1,2,3-benzotriazol-6-yl)-1H- pyrazol-3-yl]methoxy)-2- methylpropanoateF-117 Methyl 2-([1-[2-(dimethyl- H-82 LC-MS: (ES, m/z): 478.3.amino)phenyl]-5-(1-ethyl-1H- indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate Alcohol Product F-23 Methyl2-([5-[3-(2,2-dimethylpropoxy)phenyl]-1- H-83(quinolin-8-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-101Methyl 2-([1-[(2-chlorophenyl)methyl]-5-[5-(2- H-84Methylpropoxy)thien-2-yl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoateF-102 Methyl 2-(1-[(2-chlorophenyl)-5-[2-(2-methylpropyl)- H-851,3-oxazol-5-yl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-103Methyl 2-(1-[(2-chlorophenyl)methyl]-5-[2-(2-methyl- H-86propoxy)-1,3-thiazol-5-yl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoateF-104 Methyl 2-([1-(2-chlorophenyl)-5-[3-(2-methyl- H-87propoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate F-1052-([5-Benzyl-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3- H-88yl]methoxy)-2-methylpropanoic acid F-110 Methyl2-[1-[(2,6-dimethoxyphenyl)methyl]-5-[3-(2- H-89methylpropoxy)phenyl]-1H-pyrazol-3-yl)methoxy)-2- methylpropanoate F-111Methyl 2-[(1-[[4-(dimethylamino)phenyl]methyl]-5-[3- H-90(2-methylpropoxy)phenyl]-1H-pyrazol-3-yl)methoxy)-2- methylpropanoateF-112 Methyl 2-(1-[[2-(dimethylamino)-6-fluorophenyl]- H-91methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3- yl)methoxy)-2-methylpropanoate F-113 Methyl (1-[(2-chlorophenyl)methyl]-5-phenoxy-1H- H-92pyrazol-3-yl)methoxy)-2-methyl-propanoate F-114 Methyl2-[(5-[[(tert-Butoxy)carbonyl](phenyl)amino]-1- H-93[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl)methoxy)-2- methylpropanoateF-115 Methyl 2-[(1-[(3-chloropyridin-2-yl)methyl]-5-(3- H-94methoxyphenyl)-1H-pyrazol-3-yl)methoxy)-2- methylpropanoate F-7 Methyl2-([1-[(2-chlorophenyl)methyl]-5-(3-nitro- H-95phenyl)-1H-pyrazole-3-yl]methoxy)-2-methylpropanoate

The following esters of 2-hydroxy-2-methylbutanoic acid were prepared.

Methyl 2-hydroxy-2-methylbutanoate

To a solution of 2-hydroxy-2-methyl-butanoic acid (3.0 g, 25.40 mmol,1.00 equiv) in MeOH (100 mL) was added H₂SO₄ (3 mL) dropwise withstirring at 0° C. The resulting solution was heated to reflux for 16 h,cooled, concentrated under vacuum, diluted with 200 mL of EtOAc, washedwith 1×100 mL of (sat)NaHCO₃(aq), dried over Na₂SO₄, and concentratedunder vacuum to afford 780 mg (23%) of the title compound as a colorlessoil.

Methyl (2R)-2-hydroxy-2-methylbutanoate

To a solution of (2R)-2-hydroxy-2-methylbutanoic acid (1.0 g, 8.47 mmol,1.00 equiv) in MeOH (50 mL) was added SOCl₂ (2.0 g, 2.00 equiv) dropwisewith stirring at 0° C. The resulting solution was heated to reflux for16 h, then concentrated under vacuum, diluted with 100 mL of CH₂Cl₂. Themixture was dried over Na₂SO₄ and concentrated under vacuum, affording700 mg (63%) of the title compound as a colorless oil. ¹H-NMR: (300 MHz,CDCl₃) δ: 3.79 (s, 3H), 3.04 (s, 1H), 1.89-1.61 (m, 2H), 1.41 (s, 3H),0.88 (t, J=7.4 Hz, 3H).

Methyl (2S)-2-hydroxy-2-methylbutanoate

To a solution of (2S)-2-hydroxy-2-methylbutanoic acid (500 mg, 4.23mmol, 1.00 equiv) in MeOH (30 mL) was added SOCl₂ (1.03 mg, 0.01 mmol,2.00 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred for 16 h at 60° C., then concentrated under vacuum, diluted with200 mL of CH₂Cl₂, washed with 1×100 mL of (sat)NaHCO₃(aq), andevaporated under reduced pressure. The solid that formed was dried in anoven under reduced pressure, affording 400 mg (72%) of the titlecompound as colorless oil. LC-MS: (ES, m/z): 132. ¹H NMR (DMSO) δ: 5.10(s, 1H), 3.62 (s, 3H), 1.73-1.44 (m, 2H), 1.24 (s, 3H), 0.78 (t, J=7.4Hz, 3H).

The following substituted pyrazole carboxylic esters were obtained fromWilliamson ether synthesis of the corresponding (bromomethyl)pyrazolewith HO—C(CH3)2COOMe:

TABLE 16 Ether synthesis from (bromomethyl) pyrazoles. Bromo cpd ProductSpectral G-3 Methyl 2-methyl-2-([5-[3-(2-methylpropoxy)- H-96 LC-MS:(ES, phenyl]-1-phenyl-1H-pyrazol-3-yl]methoxy)- m/z): 423. propanoateG-5 Ethyl (2R)-2-([1-(2-bromophenyl)-5-(1-propyl- H-97 LC-MS: (ES,1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2- m/z): 541.1.methylbutanoate (This reaction was performed with Methyl(2R)-2-hydroxy-2-methylbutanoate) G-6 Methyl2-([1-(2-fluorophenyl)-5-[3-(2-methyl- H-98 LC-MS: (ES,propoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- m/z): 441. methylpropanoateG-9 Methyl 2-([5-(3-methoxyphenyl)-1-[2-(propan-2- H-99 LC-MS: (ES,yloxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- m/z): 439. methylpropanoateG-22 Methyl 2-[3-(bromomethyl)-1-[(2-chlorophenyl)- H-100methyl]-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoate G-10 Methyl 2-([1-(2-chlorophenyl)-5-(3-H-101 cyclopropoxyphenyl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoateG-12 Methyl (2R)-2-([1-(2-bromophenyl)-5-(3-cyclo- H-102 LC-MS: (ES,propoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- m/z): 499.3. methylbutanoateG-13 Methyl 2-([5-(3-cyclopropoxyphenyl)-1-(2- H-103 LC-MS: (ES,methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- m/z): 437. methylpropanoateG-25 Methyl 2-([5-(3-methoxyphenyl)-1-(2-methyl- H-104propyl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoate G-26 Methyl2-([5-(3-methoxyphenyl)-1-([oxan-4-yl]- H-105methyl)-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoate G-15 Methyl2-([1-[(2-cyclopropoxyphenyl)methyl]-5- H-106 LC-MS: (ES,(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- m/z): 451.methylpropanoate G-16 Methyl 2-([1-[(2-chlorophenyl)methyl]-5-(3,5-H-107 LC-MS: (ES, dimethoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- m/z):459. methylpropanoate G-17 Methyl 2-([1-[(2-chlorophenyl)methyl]-5-(1-H-108 LC-MS: (ES, methyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]- m/z): 453.methoxy)-2-methylpropanoate G-20 Methyl2-([1-[(2-chlorophenyl)methyl]-5-[2- H-109 LC-MS: (ES,(propan-2-yloxy)-1,3-oxazol-5-yl]-1H-pyrazol-3- m/z): 448.yl]methoxy)-2-methylpropanoate G-2 Methyl2-([1-[(2-chlorophenyl)methyl]-5-[1,3- H-110 LC-MS: (ES,dimethyl-1H-thieno[2,3-c]pyrazol-5-yl]-1H- m/z): 473.pyrazol-3-yl]methoxy)-2-methylpropanoate G-27 Methyl2-([5-(3-cyclopropoxyphenyl)-1-[[2- H-111 LC-MS: (ES,(dimethylamino)phenyl]methyl]-1H-pyrazol-3- m/z): 464.yl]methoxy)-2-methylpropanoate G-21 Methyl2-([5-(3-cyclopropoxyphenyl)-1-[2- H-112 LC-MS: (ES,(dimethylamino)phenyl]-1H-pyrazol-3-yl]- m/z): 450methoxy)-2-methylpropanoate G-24 Methyl2-([5-(3-methoxyphenyl)-1-[[2-(propan- H-1132-yloxy)phenyl]methyl]-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoate

Intermediate H-114: Methyl2-([1-[(2-chlorophenyl)methyl]-5-(4-cyclopropoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

tert-Butyl2-([1-[(2-chlorophenyl)methyl]-5-(4-bromothien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of tert-butyl 2-hydroxy-2-methylpropanoate (2.14 g, 13.36mmol, 3.00 equiv) in THF (50 mL) was added NaH (535 mg, 13.38 mmol, 3.00equiv), in portions at 0° C. The mixture was stirred at 0° C. for 20min. To this was added Int G-23 (2 g, 4.48 mmol, 1.00 equiv) at 0° C.and Bu₄NI (1.0 g, 2.72 mmol, 0.50 equiv). The resulting solution wasstirred for 16 h at rt then quenched by the addition of water/ice. Theresulting solution was extracted with 500 mL of EtOAc, and the organiclayers were combined and dried over anhydrous Na₂SO₄ and concentratedunder vacuum. The residue was applied onto a silica gel column withEtOAc/petroleum ether (1:2). This resulted in the title compound as ayellow oil (400 mg, 17%).

Methyl2-([5-(4-bromothien-2-yl)-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of the product from the previous step (400 mg, 0.76 mmol,1.00 equiv) in MeOH (20 mL) was added aq HCl (1 mL) dropwise withstirring at rt. The resulting solution was stirred for 3 h at 65° C.,concentrated under vacuum, and diluted with 100 mL of EtOAc. The pHvalue of the solution was adjusted to 7-8 with (sat) NaHCO₃(aq). Themixture was dried over anhydrous Na₂SO₄ and concentrated under vacuum.This resulted in the title compound as a yellow oil (350 mg, 95%).

Methyl2-([1-[(2-chlorophenyl)methyl]-5-(4-cyclopropoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of the product from the previous step (350 mg, 0.72 mmol,1.00 equiv) in dioxane (10 mL) was added stepwise Cs₂CO₃ (473 mg, 1.45mmol, 2.00 equiv), 2nd Generation XantPhos precatalyst (322 mg, 0.36mmol, 0.50 equiv), and cyclopropanol (168 mg, 2.89 mmol, 4.00 equiv).The final reaction mixture was irradiated with microwave radiation for 1h at 85° C. The resulting solution was diluted with 100 mL of EtOAc. Theresulting mixture was washed with 2×100 mL of brine. The mixture wasdried over anhydrous Na₂SO₄ and concentrated under vacuum. The residuewas applied onto a silica gel column with EtOAc/petroleum ether (1:2).This resulted in the title compound as a yellow oil (150 mg, 45%).

Intermediate H-115: Methyl2-([5-(3-aminophenyl)-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of Int. H-95 (400 mg, 0.90 mmol, 1.00 equiv) in AcOH/H₂O(10/1 mL) was added Zn (400 mg, 6.15 mmol), in portions at roomtemperature. The resulting mixture was stirred for 2 h at roomtemperature. The solids were removed by filtration. The pH value of thesolution was adjusted to 7-8 with sat NaHCO₃. The resulting solution wasextracted with 100 mL of EtOAc, and the organic layers were combined,washed with 2×200 mL of brine, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The residue was purified by Prep-TLC withDCM/MeOH (30:1), affording 230 mg (62%) of the title product as a yellowoil.

Intermediate H-116: Methyl2-([1-[(2-chlorophenyl)methyl]-5-[3-(2-methylpropanamido)-phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

A solution of Int. H-115 (200 mg, 0.48 mmol, 1.00 equiv), HATU (276 mg,0.73 mmol, 1.50 equiv), 2-methylpropanoic acid (130 mg, 1.48 mmol, 3.00equiv) and DIEA (187 mg, 1.45 mmol, 3.00 equiv) in DMF (20 mL) wasstirred overnight at rt, then diluted with 200 mL of EtOAc, washed with2×100 mL of brine, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The residue was purified by Prep-TLC with DCM/MeOH (30:1), toafford 155 mg (66%) of the title product as a yellow solid.

Intermediate H-117: Methyl2-([1-[(2-chlorophenyl)methyl]-5-[3-(methylsulfanyl)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of Int. H-115 (700 mg, 1.69 mmol, 1.00 equiv) in MeCN (10mL). was added dimethyl disulfide (319 mg, 3.39 mmol, 2.00 equiv). Theresulting mixture was heated 60° C. for 1 h, then cooled to rt.tert-Butyl nitrite (350 mg, 3.40 mmol, 2.00 equiv) was then addeddropwise with stirring, and the resulting solution was stirred for 3 hat 60° C., then diluted with 200 mL of EtOAc, washed with 2×100 mL ofbrine, dried over anhydrous Na₂SO₄ and concentrated under vacuum. Theresidue was applied onto Prep-TLC with EtOAc/petroleum ether (1:2). Thisresulted in 300 mg (40%) of the title product as a yellow oil.

Intermediate H-118: Methyl2-([1-[(2-chlorophenyl)methyl]-5-(3-methanesulfonylphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of Int. H-117 (300 mg, 0.67 mmol, 1.00 equiv) in MeOH/H₂O(10/5 mL) was added K₂S₂O₈ (233 mg, 1.53 mmol, 1.00 equiv), in portionsat rt. The resulting solution was stirred for 2 h, then diluted with 200mL of EtOAc, washed with 2×100 mL of brine, dried over anhydrous Na₂SO₄and concentrated under vacuum. The residue was applied onto Prep-TLCwith EtOAc/petroleum ether (1:3). This resulted in 180 mg (58%) of thetitle product as a yellow solid.

Intermediate H-119: Methyl2-([1-[(2-chlorophenyl)methyl]-5-(3-methanesulfonamidophenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of Int. H-115 (200 mg, 0.48 mmol, 1.00 equiv), pyridine(75 mg, 0.95 mmol, 2.00 equiv), and DMAP (6 mg, 0.05 mmol, 0.10 equiv)in DCM (10 mL). was added methanesulfonyl chloride (83 mg, 0.72 mmol,1.50 equiv) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at rt, then diluted with 100 mL of DCM, washed with2×100 mL of brine, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The residue was applied onto Prep-TLC with EtOAc/petroleum ether(1:4). This resulted in 100 mg (42%) of the title product as a yellowoil.

Intermediate H-120: Methyl2-([1-[(2-chlorophenyl)methyl]-5-[3-(methylamino)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of Int. H-115 (200 mg, 0.48 mmol, 1.00 equiv) in MeOH (10mL) was added paraformaldehyde (107 mg, 2.43 mmol, 5.00 equiv), followedby the addition of MeONa (0.45 mL, 5.00 equiv, 5.4M) dropwise withstirring at room temperature. The resulting solution was stirred for 2 hat 60° C., then cooled to 0° C. NaBH₄ (92 mg, 2.43 mmol, 5.00 equiv) wasadded, and the solution was stirred for 1 h at 60° C., then cooled,diluted with 100 mL of EtOAc, washed with 2×50 mL of brine, dried overanhydrous Na₂SO₄ and concentrated under vacuum. The residue was appliedonto Prep-TLC with EtOAc/petroleum ether (1:4). This resulted in 100 mg(48%) of the title product as a yellow oil.

Intermediate H-121: Methyl2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-ethylbutanoate

Methyl 2-ethyl-2-hydroxybutanoate

To a solution of 2-ethyl-2-hydroxybutanoic acid (2.0 g, 15.13 mmol, 1.00equiv) in MeOH (100 mL) was added H₂SO₄ (3 mL) dropwise with stirring atrt. The resulting solution was heated to reflux for 16 h, thenconcentrated under vacuum, diluted with 200 mL of EtOAc, washed with2×100 mL of sat NaHCO₃, dried over anhydrous Na₂SO₄ and concentratedunder vacuum, affording 800 mg (36%) of the title product as a colorlessoil.

Methyl2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-ethylbutanoate

To a solution of methyl 2-ethyl-2-hydroxybutanoate (371 mg, 2.54 mmol,2.00 equiv) in DMF/THF (7/7 mL) was added NaH (100 mg, 4.17 mmol, 2.00equiv) at 0° C. in 30 min. To this was added NaI (140 mg) and Int. G-1(500 mg, 1.28 mmol, 1.00 equiv). The resulting solution was stirred for16 h at rt. The residue was applied onto a Prep-TLC with EtOAc/petroleumether (1:10). The collected fractions were combined and concentratedunder vacuum. This resulted in 210 mg (38%) of the title product as awhite liquid.

Intermediate H-122: Methyl(2R)-2-([5-(3-cyclopropoxyphenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate

Methyl(2R)-2-([5-(3-cyclopropoxyphenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate

To a solution of methyl (2R)-2-hydroxy-2-methylbutanoate (250 mg, 1.89mmol, 2.00 equiv) in THF (20 mL) was added NaH (76 mg, 1.90 mmol, 2.00equiv), in portions at 0° C. The mixture was stirred at 0° C. for 20min, then Int. F-10 (400 mg, 0.94 mmol, 1.00 equiv) at 0° C., Bu₄NI (200mg, 0.54 mmol, 0.50 equiv) was added. The resulting solution was stirredfor 16 h at rt, then quenched by the addition of water/ice. Theresulting solution was extracted with 100 mL of ethyl acetate, and thecombined organic layers were dried over Na₂SO₄, concentrated undervacuum, and purified with Prep-TLC using EtOAc/petroleum ether (1:1) toafford 160 mg (36%) of the title compound as a yellow solid. LC-MS: (ES,m/z): 475.

The following substituted pyrazole carboxylic esters were obtained fromWilliamson ether synthesis of the corresponding (bromomethyl)pyrazolewith HO—C(CH3)(Et)COOMe:

TABLE 17 Ether synthesis from (bromomethyl) pyrazoles. Bromo cpd ProductSpectral G-1 Methyl (2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3- H-123LC-MS: (ES, methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- m/z): 443.methylbutanoate G-1 Methyl (2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-H-124 LC-MS: (ES, methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methyl-m/z): 443. butanoate G-4 Ethyl (2R)-2-([1-(2-bromophenyl)-5-(1-ethyl-1H-H-125 LC-MS: (ES, indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2- m/z): 525.methylbutanoate G-7 Methyl (2R)-2-([5-[3-(2,2-dimethylpropoxy)phenyl]-1-H-126 LC-MS: (ES, (1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-m/z): 505. 2-methylbutanoate G-8 Ethyl(2R)-2-methyl-2-([1-(1-methyl-1H-indazol-7-yl)- H-127 LC-MS: (ES,5-[3-(2-methylpropoxy)phenyl]-1H-pyrazol-3- m/z): 505.15.yl]methoxy]butanoate G-10 Ethyl (2R)-2-([1-(2-chlorophenyl)-5-(3- H-128LC-MS: (ES, cyclopropoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- m/z): 469.1.methylbutanoate G-11 Methyl (2R)-2-([1-(2-chlorophenyl)-5-(3,5- H-129LC-MS: (ES, dimethoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- m/z): 459.methylbutanoate G-18 Methyl(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl- H-130 LC-MS: (ES,1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2- m/z): 481. methylbutanoateG-18 Methyl (2S)-2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl- H-1311H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2- methylbutanoate G-19 Ethyl(2R)-2-([5-(3,5-dimethoxyphenyl)-1-[(2- H-132 LC-MS: (ES,ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2- m/z): 497.5.methylbutanoate

Intermediate H-133: Methyl2-([1-[2-(azetidin-1-yl)phenyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

Into a 20-mL sealed tube were combined methyl2-([1-(2-bromophenyl)-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate(200 mg, 0.40 mmol, 1.00 equiv) L-proline (46 mg, 0.40 mmol, 1.00equiv), CuI (38 mg, 0.20 mmol, 0.50 equiv), K₂CO₃ (166 mg, 1.20 mmol,3.00 equiv), azetidine (69 mg, 1.21 mmol, 3.00 equiv), and DMSO (10 mL).The resulting solution was stirred overnight at 70° C. The reactionmixture was cooled to room temperature. The resulting solution wasextracted with 3×20 mL of EtOAc and the organic layers combined anddried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by prep-TLC with EtOAc/petroleum ether (1/3). This resulted in50 mg (26%) of the title compound as light yellow oil. LC-MS: (ES, m/z):474. ¹H NMR: (300 MHz, CDCl₃) δ 7.90 (s, 1H), 7.62 (d, J=8.4 Hz, 1H),7.34 (s, 1H), 7.24 (m, 2H), 7.07 (dd, J=7.8, 1.5 Hz, 1H), 6.76 (s, 1H),6.69 (td, J=7.6, 7.5, 1.3 Hz, 1H), 6.45 (dd, J=8.2, 1.3 Hz, 1H), 4.63(s, 2H), 4.25 (q, J=7.3, 7.3, 7.3 Hz, 2H), 3.79 (s, 3H), 3.58 (dq,J=24.9, 7.4, 7.3, 7.3 Hz, 4H), 2.10 (p, J=7.3, 7.3, 7.3, 7.3 Hz, 2H),1.56 (s, 6H), 1.34 (q, J=8.2, 8.2, 7.2 Hz, 3H).

Intermediate H-134: Methyl2-[1-[2-(azetidin-1-yl)phenyl]-5-[3-(2,2-dimethylpropoxy)-phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

Into a 30-mL sealed tube were combined Int. H-4 (200 mg, 0.39 mmol, 1.00equiv), L-proline (44 mg, 0.38 mmol, 1.00 equiv), CuI (40 mg, 0.21 mmol,0.50 equiv), K₂CO₃ (160 mg, 1.16 mmol, 3.00 equiv), azetidine (66 mg,1.16 mmol, 3.00 equiv), and DMSO (10 mL). The resulting solution wasstirred overnight at 70° C., cooled, and extracted with 3×15 mL ofEtOAc. The combined organic layers were dried over Na₂SO₄, concentratedunder vacuum, and purified with by prep-TLC using EtOAc/petroleum ether(1/3) to afford 70 mg (37%) of the title compound as a light yellow oil.LC-MS: (ES, m/z): 492.30. ¹H NMR: (300 MHz, DMSO) δ 7.28 (ddd, J=8.5,7.4, 1.6 Hz, 1H), 7.20 (t, J=7.9, 7.9 Hz, 1H), 6.98 (ddd, J=9.9, 7.2,1.5 Hz, 2H), 6.84 (m, 2H), 6.69 (m, 2H), 6.51 (dd, J=8.3, 1.3 Hz, 1H),4.44 (s, 2H), 3.71 (s, 3H), 3.50 (m, 2H), 3.42 (m, 2H), 2.07 (m, 2H),1.45 (s, 6H), 0.94 (s, 9H).

The following amino substituted aryl compounds were obtained through useof similar copper(I) mediated coupling procedures.

TABLE 18 Arylamine synthesis from (bromoaryl) pyrazoles. Aryl halideAmine Product Spectral H-2 Pyrrolidine Methyl2-([5-(1-ethyl-1H-indazol-6-yl)- H-135 LC-MS:1-[2-(pyrrolidin-1-yl)phenyl]-1H- (ES, m/z): pyrazol-3-yl]methoxy)-2-488.15. methylpropanoate H-3 Pyrrolidine Methyl2-methyl-2-([5-(1-methyl-1H- H-136 LC-MS:indazol-6-yl)-1-[2-(pyrrolidin-1-yl)- (ES, m/z):phenyl]-1H-pyrazol-3-yl]methoxy]- 474. propanoate H-24 PyrrolidineMethyl 2-([5-(3,5-dimethoxyphenyl)-1- H-137 LC-MS:[2-(pyrrolidin-1-yl)phenyl]-1H-pyrazol- (ES, m/z):3-yl]methoxy)-2-methylpropanoate 480. H-24 Azetidine Methyl2-([1-[2-(azetidin-1-yl)phenyl]- H-138 LC-MS:5-(3,5-dimethoxyphenyl)-1H-pyrazol-3- (ES, m/z):yl]methoxy)-2-methylpropanoate 466. H-25 Azetidine Methyl2-([1-[2-(azetidin-1-yl)phenyl]- H-139 LC-MS:5-(1-propyl-1H-indazol-6-yl)-1H- (ES, m/z): pyrazol-3-yl]methoxy)-2-488.1. methylpropanoate H-25 Pyrrolidine Methyl2-methyl-2-([5-(1-propyl-1H- H-140 LC-MS:indazol-6-yl)-1-[2-(pyrrolidin-1- (ES, m/z): yl)phenyl]-1H-pyrazol-3-502.2. yl]methmoxy]propanoate H-26 Azetidine Methyl2-([1-[2-(azetidin-1-yl)phenyl]- H-141 LC-MS:5-(3-cyclobutoxyphenyl)-1H-pyrazol-3- (ES, m/z):yl]methoxy)-2-methylpropanoate 476.5. H-46 Pyrrolidine Methyl2-([5-(3-cyclopropoxyphenyl)- H-142 LC-MS:1-[2-(pyrrolidin-1-yl)phenyl]-1H- (ES, m/z): pyrazol-3-yl]methoxy)-2-476.4. methylpropanoate H-46 Azetidine methyl2-([1-[2-(azetidin-1-yl)phenyl]- H-143 LC-MS:5-(3-cyclopropoxyphenyl)-1H-pyrazol- (ES, m/z):3-yl]methoxy)-2-methylpropanoate 462.15. H-46 (3S)-3- Methyl2-([5-(3-cyclopropoxyphenyl)- H-144 LC-MS: hydroxy-1-[2-[(3S)-3-hydroxypyrrolidin-1-yl]- (ES, m/z): pyrrolidinephenyl]-1H-pyrazol-3-yl]methoxy)-2- 492. methylpropanoate H-46Morpholine Methyl 2-([5-(3-cyclopropoxyphenyl)- H-145 LC-MS:1-[2-(morpholin-4-yl)phenyl]-1H- (ES, m/z): pyrazol-3-yl]methoxy)-2-492.5. methylpropanoate H-46 2-Oxo- Methyl 2-([5-(3-cyclopropoxyphenyl)-H-146 LC-MS: pyrrolidine 1-[2-(2-oxopyrrolidin-1-yl)phenyl]-1H- (ES,m/z): pyrazol-3-yl]methoxy)-2- 490.1. methylpropanoate H-46 PyrazoleMethyl 2-([5-(3-cyclopropoxyphenyl)- H-147 LC-MS:1-[2-(1H-pyrazol-1-yl)phenyl]-1H- (ES, m/z): pyrazol-3-yl]methoxy)-2-473.25. methylpropanoate H-46 (3R)-3- Methyl2-([5-(3-cyclopropoxyphenyl)- H-148 LC-MS: hydroxy-1-[2-[(3R)-3-hydroxypyrrolidin-1-yl]- (ES, m/z): pyrrolidinephenyl]-1H-pyrazol-3-yl]methoxy)-2- 492. methylpropanoate H-47 AzetidineMethyl 2-([1-[2-(azetidin-1-yl)-4- H-149 LC-MS:fluorophenyl]-5-(3-cyclopropoxy- (ES, m/z):phenyl)-1H-pyrazol-3-yl]methoxy)-2- 480.40. methylpropanoate H-20Pyrrolidine Methyl 2-([5-(3-cyclopropoxyphenyl)- H-150 LC-MS:1-[[2-(pyrrolidin-1-yl)phenyl]methyl]- (ES, m/z):1H-pyrazol-3-yl]methoxy)-2-methyl- 490.15. propanoate H-68 PyrrolidineMethyl 2-([5-(3-cyclobutoxyphenyl)-1- H-151 LC-MS:[[2-(pyrrolidin-1-yl)phenyl]methyl]-1H- (ES, m/z):pyrazol-3-yl]methoxy)-2- 504. methylpropanoate H-97 Azetidine Ethyl(2R)-2-([1-[2-(azetidin-1- H-152 LC-MS:yl)phenyl]-5-(1-propyl-1H-indazol-6- (ES, m/z):yl)-1H-pyrazol-3-yl]methoxy)-2- 516.5. methylbutanoate H-102 AzetidineMethyl (2R)-2-([1-[2-(azetidin-1- H-153 LC-MS:yl)phenyl]-5-(3-cyclopropoxyphenyl)- (ES, m/z):1H-pyrazol-3-yl]methoxy)-2- 476.2. methylbutanoate H-125 PyrrolidineEthyl (2R)-2-([5-(1-ethyl-1H-indazol-6- H-154 LC-MS:yl)-1-[2-(pyrrolidin-l-yl)phenyl]-1H- (ES, m/z):pyrazol-3-yl]methoxy)-2- 516. methylbutanoate H-125 Azetidine Ethyl(2R)-2-([1-[2-(azetidin-1- H-155 LC-MS:yl)phenyl]-5-(1-ethyl-1H-indazol-6-yl)- (ES, m/z):1H-pyrazol-3-yl]methoxy)-2- 502. methylbutanoate

Intermediate H-156: Methyl2-([1-(2-cyanophenyl)-5-(3-cyclopropoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

To a solution of Int. H-46 (150 g, 309.04 mmol, 1.00 equiv) and Zn(CN)₂(72 mg, 0.62 mmol, 2.00 equiv) in DMF (15 mL) was added Pd(PPh₃)₄ (36mg, 0.03 mmol, 0.10 equiv), in portions at rt. The resulting solutionwas stirred for 16 h at 100° C., diluted with 100 mL of EtOAc, washedwith 2×50 mL of (sat)FeSO₄(aq), dried over Na₂SO₄ and concentrated undervacuum. The residue was applied onto a Prep-TLC with EtOAc/petroleumether (1:2). This resulted in 100 mg of the title compound as colorlessoil. LC-MS: (ES, m/z): 432.

Chromatographic Procedures

All chromatography was performed on an 2#-AnalyseHPLC-SHIMADZU(HPLC-10)instrument, with detection at 254/220 nm. Columns used for purificationinclude:

“Xselect”: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 um.

“XBridge”: XBridge Prep C18 OBD Column, 19*150 mm Sum.

EXAMPLES

The invention is further illustrated by the following examples.

Example 1:2-([1-[(3-Chlorophenyl)methyl]-5-phenyl-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

To a solution of Int. H-1 (0.068 g, 0.170 mmol) in THF:MeOH:H₂O (2:1:1)(8 mL) was added LiOH*H₂O (0.035 g, 0.85 mmol) at RT and stirring wascontinued for further 3 h. The solvent was then evaporated and to theresidue water (2 mL) was added and acidified with 1M citric acid. Themixture was extracted with EtOAc (25 mL) and washed with water (10 mL)followed by brine (10 mL). The EtOAc layer was dried over Na₂SO₄, andsolvent was removed by evaporation. The crude product waschromatographed over SiO₂ (ISCO CombiFlash® Rf 200) using 0-30% gradientof MeOH in DCM to afford the title product as white solid (0.032 g).¹HNMR (CDCl₃): δ 1.56 (s, 6H), 4.61 (s, 2H), 5.34 (s, 2H), 6.38 (s, 1H),6.87-6.97 (m, 1H), 7.04 (s, 1H), 7.18-7.24 (m, 2H), 7.26-7.35 (m, 2H),7.35-7.45 (m, 3H).

Examples 2-50 were prepared analogously as described in Example 1.

TABLE 19 Examples 2-50. IUPAC Name Ex. Structure Analytical data  2

2-([5-(4-Chlorophenyl)-1-[(4-chlorophenyl)-methyl]1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H NMR (CD₃OD,400 MHz) δ 1.52(s, 6H), 4.54(s, 2H0, 5.329s, 2H), 6.48(s, 1H), 6.91-7.00(m, 1H), 7.21-7.30-(m, 2H), 7.31-7.38(m, 2H), 7.40-7.48 (m 3H).  3

2-([5-(4-Chlorophenyl)-1-[(2-chlorophenyl)-methyl]1H-pyrazol-3-yl]methoxy)-2-methyl- propanoic acid ¹H NMR (CD₃OD,400 MHz) δ 1.50(s, 6H), 4.58(s, 2H), 5.41(s, 2H), 6.56(s, 1H), 6.72-6.80 (m, 1H), 7.20-7.34(m, 2H), 7.34-50 (m, 5H).  4

2-([1-[(2-Chlorophenyl)methyl]-5-(4-fluorophenyl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H NMR(CD₃OD, 400 MHz) δ1.51(s, 6H), 4.58(s, 2H), 5.40(s, 2H), 6.55(s, 1H),6.70- 6.78(m, 1H), 7.14-7.18(m, 2H), 7-20-7.29(m, 2H), 7.32-7.40(m, 3H). 5

2-([5-(4-Chlorophenyl)-1-[(2,4- dichlorophenyl)methyl]1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H NMR (CD₃OD, 400 MHz) δ 1.48(s,6H), 4.58(s, 2H), 5.40 (s, 2H), 6.54(s, 1H), 6.73(d, 1H), 7.20-7.38 (m,3H), 7.40-48 (m, 3H).  6

2-([5-(4-Chlorophenyl)-1-[(2,4- dichlorophenyl)methyl]1H-pyrazol-3-yl]methoxy]acetic acid ¹H NMR (DMSO-d₆, 400 MHz) δ 3.80 (s, 2H), 4.509s, 2H), 5.30 (s, 2H), 6.50 (s, 1H), 6.60-80 (m, 1H), 7.20-70 (m, 6H). 7

2-([1-Benzyl-5-(4-Chlorophenyl)1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H NMR (CD₃OD, 400 MHz) δ 1.53(s,6H), 4.58(s, 2H), 5.38 (s, 2H), 6.51(s, 1H), 6.90(d, 2H), 7.18-7.50 (m,7H).  8

2-([1-[(2-Chlorophenyl)methyl]-5-phenyl-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H NMR (DMSO-d₆, 400 MHz)δ1.56 (s, 6H), 4.58(s, 2H), 5.41(s, 2H), 6.56(s, 1H), 6.75- 6.78(m, 1H),7.20-7.30 (m, 4H), 7.32-7.43(m, 4H). 1H NMR (CD3OD, 400 MHz) δ 1.54(s,6H), 4.589s, 2H), 5.40(s, 2H), 6.55(s, 1H), 6.68- 6.74(m, 1H),7.20-7.42(m, 8H).  9

2-([5-(2-Chlorophenyl)-1-[(2- chlorophenyl)methyl]1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H NMR (CD₃OD, 400 MHz) δ 1.53(s,6H), 4.58(s, 2H), 5.28(s, 2H), 6.43(s, 1H), 6.78- 7.81(m, 1H),7.16-34(m, 5H), 7.38-7.42 (m, 1H), 7.50-7.56(m, 1H). 10

2-([5-(3-Chlorophenyl)-1-[(2- chlorophenyl)methyl]1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H NMR (CD₃OD, 400 MHz) δ1.32 (S,6h)4.58(s, 2H), 5.42(s, 2H), 6.57(s, 1H), 6.67- 6.80 (m, 1H), 7.22-7.30(m, 3H), 7.32-42(m, 4H). 11

2-([1-[(2-Chlorophenyl)methyl]-5-(m- tolyl)1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H NMR (CDCl₃, 400 MHz) δ 1.58 (s, 6H), 2.35 (s,3H), 4.61 (s, 2H), 5.42 (s, 2H), 6.39 (s, 1H), 6.75-6.84 (m, 1H),7.00-7.12 (m, 2H), 7.18-7.29 (4H), 7.29-7.38 (m, 1H). 12

2-([1-[(2-Chlorophenyl)methyl]-5-(3-fluorophenyl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H NMR(CDCl₃, 400 MHz) δ 1.58(s, 6H), 4.64 (s, 2H), 5.48 (s, 2H), 6.42 (s,1H), 6.72- 6.85 (m, 1H), 6.88-7.14 (m, 3H), 7.14-7.40 (m, 4H). 13

2-([1-[(2-Chlorophenyl)methyl]-5-[3-(trifluoromethyl)phenyl]1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acid¹H NMR (CDCl₃, 400 MHz) δ 1.58 (s, 6H), 4.62 (s, 2H), 5.41 (s, 2H), 6.46(s, 1H), 6.80- 6.88 (m, 1H), 7.17-7.24(m, 2H), 7.29-7.38 (m, 1H),7.39-7.47 (m, 1H), 7.49-7.54 (m, 2H), 7.59-7.68 (m, 1H). 14

2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H NMR(CDCl₃, 400 MHz) δ 1.58 (s, 6H), 3.68 (s, 3H), 4.62 (s, 2H), 5.46 (s,2H), 6.42 (s, 1H), 6.74-6.81 (m, 2H), 6.82-6.88 (m, 1H), 6.89-6.94 (m,1H), 7.15-7023 (m, 2H), 7.26- 7.37 (m, 2H). 15

2-([1-[(2-Chlorophenyl)methyl]-5-cyclohexyl-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H NMR (CDCl₃, 400 MHz)δ1.16-1.42 (m, 4H), 1.54 (s, 6H), 1.57-1.81 (m, 5H), 2.36- 2051 (m, 1H),2.76-2.91 (m, 1H), 4.56 (s, 2H), 5.39 (s, 2H), 6.15 (s, 1H), 6.54-6.68(m, 1H), 7.08-7.25 (m, 2H), 7.31-7.44 (m, 1H). 16

2-([1-[(2-Chlorophenyl)methyl]-5-cyclopentyl-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H NMR(CDCl₃, 400 MHz) δ 1.22-1.64(m, 10H), 1.64-1.80(m, 2H), 1.82-2.00(m,2H), 2.80-2.92(m, 1H), 4.74(s, 2H), 5.40(s, 2H), 6.10(s, 1H),6.58-6.62(m, 1H), 7.10-7.22(m, 2H), 7.38(d, 1H). 17

1-[[5-(4-Chlorophenyl)-1-[(2- chlorophenyl)methyl]1H-pyrazol-3-yl]methoxy]cyclopropanecarboxylic acid ¹H NMR (CD₃OD, 400 MHz)δ1.18-1.32(m, 3H), 1.64-1.80(m, 1H), 4.61(s, 2H), 5.42(s, 2H), 6.52(s,1H), 6.60-6.80(m, 1H), 7.20- 52(m, 7H). 18

2-([1-[(2-Chlorophenyl)methyl]-5-thiazol-2-yl-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H NMR (CDCl₃, 400MHz) δ 1.38 (m, 6H), 4.48 (s, 2H), 5.61 (s, 2H), 6.55-6.65 (m, 1H), 7.03(s, 1H), 7.09-7.16 (m, 1H), 7.17-7.23 (m, 1H), 7.27-7.33 (d, 1H),7.34-7.42 (m, 1H), 7.88-7.96 (d, 1H). 19

2-([5-(4-Chlorophenyl)-1-[(2- fluorophenyl)methyl]1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H NMR (CD₃OD, 400 MHz) δ 1.48 (s,6H), 4.53(s, 2H) 5.38(s, 2H), 6.50(s, 1H), 6.81- 6.92(m 1H),7.00-7.13(m, 2H), 7.21-7.31 (m 1H), 7.34-7.48(m 4H) 20

2-([5-(4-Chlorophenyl)-1-[(2- chlorophenyl)methyl]1H-pyrazol-3-yl]methoxy)-2-methyl-propanamide ¹H NMR (CD₃OD 400 MHz) δ 1.46(s, 6H),4.58(s, 2H), 5.40(s, 2H), 6.52(s, 1H), 6.71- 6.76(m, 1H), 7.20-7.58(m,6H) 21

2-([5-(4-chlorophenyl)-1-([pyridin-4-yl]methyl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H NMR (CD₃OD400 MHz) δ 1.52(s, 6H), 4.58(s, 2H), 5.56(s, 2H), 6.59(s, 1H), 7.21-7.52(m, 6H), 8.50 (bs, 2H) 22

2-([5-(4-Chlorophenyl)-1-([pyridin-2-yl]methyl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H NMR(DMSO-d₆, 400 MHz) δ 1.38(s, 6H), 4.40(s, 2H), 5.38(s, 2H), 6.41(s, 1H),6.90- 7.10(m, 1H), 7.20-7.85(m, 6H), 8.51(bs, 1H) 23

2-([5-(4-Chlorophenyl)-1-([pyridin-3-yl]methyl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H NMR (CD₃OD400 MHz) δ 1.52(s, 6H), 4.58(s, 2H), 5.10(s, 2H), 6.55(s, 1H), 7.30-7.41(m, 3H), 7.42-7.51(m, 3H), 8.19(s, 1H), 8.41(d, 1H). 24

2-([1-[(2-Chlorophenyl)methyl]-5-(thien-3-yl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid. ¹HNMR(CDCl₃):δ1.37(s, 6H), 4.38(s, 2H), 5.43(s, 2H), 6.48(s, 1H), 6.62-6.64(m, 1H),7.17-7.31(m, 3H), 7.44-7.46(m, 1H), 7.57- 7.64(m, 2H). 25

2-([1-[(2-Chlorophenyl)methyl]-5-(thien-2-yl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid. ¹HNMR (CDCl₃): δ1.37(s, 6H), 4.39(s, 2H), 5.47(s, 2H), 6.53(s, 1H), 6.59-6.61(m, 1H),7.09-7.14(m, 2H), 7.24-7.31(m, 2H), 7.45- 7.47(m, 1H), 7.62-7.64(m, 1H).26

2-([1-[(2-Fluorophenyl)methyl]-5-(3-(2-methylpropoxy)phenyl)1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acid¹HNMR(CDCl₃): δ 0.97 (s, 3H), 0.99(s, 3H), 1.55 (s, 6H), 2.00-2.06 (m,1H), 3.70(d, 2H), 4.62 (s, 2H), 5.39 (s, 2H), 6.37 (s, 1H), 6.79- 6.80(m, 1H), 6.87-7.09 (M, 5H), 7.22-7.30(m, 2H) 27

2-([1-[(2-Chlorophenyl)methyl]-5-(3-(2-methylpropoxy)phenyl)1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acid.¹HNMR (CDCl₃): δ 0.95(s, 3H)(, 0.96(s, 3H), 1.56(s, 6H), 1.97-2.03(m,1H), 3.49(d, 2H), 4.63 (s, 2H), 5.43(s, 2H), 6.41(s, 1H), 6.73- 6.80 (m,2H), 6.84-6.92(m, 2H), 7.19- 7.28(m, 3H), 7.33-7.35(m, 1H). 28

2-([1-[(2-Chlorophenyl)methyl]-5-(3-ethoxyphenyl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid. ¹HNMR(CDCl₃): δ 1.34 (t, 3H), , 1.56(s, 6H), 3.86(q, 2H), 4.62(s, 2H), 5.43(s, 2H), 6.40(s, 1H), 6.76-6.78 (m, 2H), 6.83-6.85(m, 1H), 6.89-6.91(m,1H), 7.19-7.28 (m, 3H), 7.33- 7.35(m, 1H). 29

2-([1-[(2-Bromophenyl)methyl]-5-(3-isopropoxyphenyl)1H-pyrazol-3-yl]methoxy)- 2-methylpropanoic acid. ¹HNMR(CDCl₃): δ 1.21(s, 3H), 1.23(s, 3H), 4.28-4.32(m, 1H), 4.62(s, 2H),5.39(s, 2H). 6.42(s, 1H), 6.71-6.74(m, 2H), 6.82- 6.89(m, 2H),7.11-7.15(m, 1H), 7.22-7.27(m, 2H), 7.51-7.54(m, 1H). 30

2-([1-[(2-Bromophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹HNMR(CDCl₃): δ 1.56(s, 6H), 3.65(s, 3H), 4.62(s, 2H), 5.39(s, 2H), 6.41(s,1H), 6.73- 6.76(m 2H), 6.84-6.92(m, 2H), 7.15(t, 1H), 7.13-7.29(m, 2H),7.52-7.54(m, 1H). 31

2-([1-[(2-Isopropylphenyl)methyl]-5-(3-methoxyphenyl)1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid. ¹HNMR(CDCl₃): δ1.13 (s, 3H), 1.15(s, 3H), 1.55 (s 6H), 2.94-2.97(m, 1H),3.62(s, 3H), 4.63(s, 2H), 5.42(s, 2H), 6.39(s, 1H), 6.65- 6.67(m, 1H),6.75-6.76(m, 1H), 6.85-6.91(m, 2H), 7.07-7.11(m, 1H), 7.21-7.28(m, 3H)32

2-([5-(3-Methoxyphenyl)-1-(o- tolylmethyl)1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. ¹HNMR (CDCl₃): δ 1.55 (s, 6H), 2.18 (s, 3H), 3.64(s, 3H), 4.62 9s, 2H), 5.31(s, 2H), 6.38(s, 1H), 6.69-6.31(m, 1H),6.77-6.78(m, 1H), 6.86-6.92 (m, 2H), 7.10-7.15 (m, 3H), 7.25- 7.29 (m,1H). 33

2-([1-[(2-Chlorophenyl)methyl]-5-[3-(cyclopropylmethoxy)phenyl]1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid. ¹HNMR (CDCl₃): δ 0.25-0.29(m, 2H), 0.58- 0.63(m, 2H),14.16-1.20(m, 1H), 1.55(s, 6H), 5.58(d, 2H), 4.63(s, 2H), 5.42(s, 2H),6.40(s, 1H), 6.374-6.78(m, 2H), 6.84-6.93(m, 2H), 7.18-7.28(m, 3H),7.33-7.35(m, 1H). 34

2-([1-[(2-Chlorophenyl)methyl]-5-[3-(trifluoromethoxy)phenyl]1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid. ¹HNMR (CDCl₃): δ1.56(6H), 4.63(s, 2H), 5.41(s, 2H), 6.46(s, 1H),6.77-6.79(m, 1H), 7.12-7.25(m, 5H), 7.32-7.35(m, 1H), 7.38-7.42 (m, 1H).35

2-([1-[(2-Chlorophenyl)methyl]-5-(3-isopropoxyphenyl)1H-pyrazol-3-yl]methoxy)- 2-methylpropanoic acid. ¹HNMR(CDCl₃): δ 1.22(s, 3H)(, 1.23(s, 3H), 1.55(s, 6H), 4.30-4.33(m, 1H),4.62(s, 2H), 5.43(s, 2H), 6.41(s, 1H), 6.75-6.90(4H), 7.19- 7.35(m, 4H).36

2-([5-(3-Methoxyphenyl)-1-[(2- methoxyphenyl)methyl]1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. ¹HNMR (CDCl₃): δ 1.55(s. 6H),3.70(s, 3H), 3.73(s, 3H), 4.62(s, 2H), 5.34(s, 2H), 6.35(s, 1H),6.77-6.392(m, 6H), 7.22-7.29(m, 2H). 37

2-([1-[(2-Chlorophenyl)methyl]-5-[3- (cyclobutoxy)phenyl]1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. ¹HNMR (CDCl₃): δ 1.49-1.61 (m, 7H),m1.75- 1.82(m 1H), 2.01-2.11(m 2H), 2.17-2.24(m 2H), 4.37-4.45(m 1H),4.62(s, 2H), 5.42(s, 2H), 6.39(s, 1H), 6.64(s, 1H), 6.75-6.86( m, 3H),7.19-7.35(m 4H). 38

2-([1-[[2-(Dimethylamino)phenyl]methyl]-5-(3-methoxyphenyl)1H-pyrazol-3-yl]methoxy)- 2-methylpropanoic acid. ¹HNMR(CDCl₃): δ 1.56(s, 6H), 2.60(s, 6H), 6.64(s, 3H), 4.63(s, 2H), 5.44(s,2H). 6.30(s, 1H), 6.71-7.11(m 6H), 7.20-7.25(m, 2H). 39

2-([1-[(2-Chlorophenyl)methyl]-5-[3- (cyclopropoxy)phenyl]1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. ¹HNMR (CDCl₃): δ 0.55-0.68(m 4H),1.55(s, 6H), 3.50-3.54(m 1H), 4.63(s, 2H), 5.44 (s, 2H), 6.42 (s, 1H),6.76-7.02( m, 4H), 7.17- 7.35 (m, 4H). 40

2-([1-[(2-Chlorophenyl)methyl]-5-[3-(morpholinomethyl)phenyl]1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid. ¹HNMR (CD₃OD): δ 1.50 (s, 6H), 3.15-3.23 (bs, 4H), 3.60-3.81 (bs,2H), 3.85-4.16(bs, 2H), 4.35(s, 2H), 4.57(s, 2H), 5.45(s, 2H), 6.60 (s,1H), 6.75 (d, 1H), 7.20-7.55 (m, 7H). 41

1-[[1-[(2-Chlorophenyl)methyl]-5-(3- methoxyphenyl)1H-pyrazol-3-yl]methoxy]cyclobutanecarboxylic acid. ¹HNMR (CDCl₃): δ 1.78-1.85 (m1H), 1.95- 2.04 (m, 2H), 2.18-2.25 (m, 1H), 3.09-3.14(m, 1H), 3.66(s,3H), 4.27-4.32 (m, 1H), 4.55-4.65 (dd, 2H), 5.43 (s, 2H), 6.44 (s, 1H),6.73- 6.91(m, 4H), 7.17-7.34 (m 4). 42

2-([1-[(2-Chlorophenyl)methyl]-5-[3-(cyclobutylmethoxy)phenyl]1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid. ¹HNMR (CDCl₃): δ 1.55(s, 6H), 1.75-1.82(m, 2H), 1.85-1.98(m, 2H),2.06-2.14(m, 2H), 2.64-2.70(m, 1H), 3.71(d, 2H), 4.63(s, 2H), 5.43(s,2H), 6.42(s, 1H), 6.75-6.92(m, 4H), 7.20-7.36(m, 4). 43

2-([1-[(2-Chlorophenyl)methyl]-5-[3-(2,2,2-trifluoroethoxy)phenyl]1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acid.¹HNMR (CDCl₃): δ 1.55(s, 6H), 4.16(q, 2H), 4.63(s, 2H), 5.42(s, 2H),6.43(s, 1H), 6.77- 6.81(m, 2H), 6.96-6.98(m, 2H), 7.19-7.36(m, 4H). 44

2-([1-[(2-Chlorophenyl)methyl]-5-[3-(cyclopentylmethoxy)phenyl]1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid. ¹HNMR (CDCl₃): δ 1.25-1.29(m, 2H), 1.55- 1.61(m, 10H),1.76-1.79(m, 2H), 2.24-2.31(m, 1H), 3.59(d, 2H), 4.62(s, 2H), 5.43(s,2H), 6.41(s, 1H), 6.73-6.91(m, 4H), 7.19-7.35(m, 4H). 45

2-([1-[(2-Chlorophenyl)methyl]-5-[3-(tetrahydropyran-4-ylmethoxy)phenyl]1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. ¹HNMR (CDCl₃): δ1.34-1.41(m, 2H), 1.55(s, 6H), 1.66-1.69(m, 2H), 1.97-1.99(m, 1H),3.38-3.46m, 2H), 3.56(d, 2H), 3.98-4.01(m, 2H), 4.62(s, 2H), 5.42(s,2H), 6.42(s, 1H), 6.71(s, 1H), 6.77-6.95(m, 3H), 7.19-7.35(m, 4H). 46

2-([1-[(2-Chlorophenyl)methyl]-5-(3-morpholinophenyl)1H-pyrazol-3-yl]methoxy)- 2-methylpropanoic acid. ¹HNMR(CDCl₃): δ 1.55(s, 6H), 2.96(t, 4H), 3.76(t, 4H), 4.62(s, 2H), 5.41(s,2H), 6.41(s, 1H), 6.68(s, 1H), 6.78-6.80(m, 2H), 6.88- 6.91(m, 1H),7.19-7.35(m, 4H). 47

2-([1-[(2-Chlorophenyl)methyl]-5-(1,3-thiazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropionic acid ¹HNMR(CDCl₃): δ 1.56(s, 6H), 4.63(s, 2H), 5.84(s, 2H), 6.62-6.67(m, 2H),7.10-7.19(m 2H), 7.33-7.35(m, 1H), 7.39(d, 1H), 8.83(d, 1H). 48

2-([1-[(2-Chlorophenyl)methyl]-5-(3-cyano-phenyl)-1H-pyrazol-3-yl]methoxy)-2- methylpropionic acid ¹HNMR(CDCl₃): δ1.56(s, 6H), 4.62(s, 2H), 5.39(s, 2H), 6.46(s, 1H), 6.82-6.84(m, 1H),7.18-7.24(m, 2H), 7.33-7.35(m 1H), 7.46- 7.55(m, 3H), 7.65-7.68(m, 1H).49

2-([1-[(2-Chlorophenyl)methyl]-5-(1,3-thiazol-5-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropionic acid¹HNMR(CDCl₃): δ 1.56(s, 6H), 4.62(s, 2H), 5.50(s, 2H), 6.60-6.6(m, 2H),7.14-7.24(m, 2H), 7.36-7.38(m, 1H), 7.76(s, 1H), 8.84(s, 1H). 50

2-([1-[(2-Chlorophenyl)methyl]-5-[3-(dimethylamino)phenyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropionic acidMS: Calculated: 427.92; Found: 428.9 [M + H].

Examples 51-74 were prepared using the methods disclosed in theindicated Schemes.

TABLE 20 Examples 51-74. IUPAC Name Ex. Scheme Structure Analytical data51 II

2-([1-[(2-Chlorophenyl)methyl]-5-[3- (propan-2-yl)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. ¹H-NMR (300 MHz, MeOD): δ 1.12 (6 H,d), 1.53 (6 H, s), 2.83 (1 H, p), 4.60 (2 H, s), 5.40 (2 H, s), 6.54 (1H, s), 6.72-6.81 (1 H, m), 7.05-7.45 (7 H, m). 52 II

2-([1-[(2-chlorophenyl)methyl]-5-[3- (methoxymethyl)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (300 MHz, MeOD): δ 1.52 (6H, s), 4.42 (2 H, s), 4.59 (2 H, s), 5.42 (2 H, s), 6.56 (1 H, s), 6.70-6.80 (1 H, m), 7.17-7.33 (4 H, m), 7.32-7.45 (3 H, m). 53 II

2-([1-benzyl-5-(3-methoxyphenyl)- 1H-pyrazol-3-yl]methoxy)-2-methyl-propanoic acid ¹H-NMR (300 MHz, MeOD) δ 1.51 (6 H, s), 3.68 (3 H, s),4.57 (2 H, s), 5.35 (2 H, s), 6.48 (1 H, s), 6.84 (1 H, dd), 6.89-7.06(4 H, m), 7.17-7.38 (4 H, m). 54 II

2-({1-[(2-Chlorophenyl)methyl]-5- (3-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl}methoxy)-2- methylpropionic acid ¹H-NMR: (300 MHz, MeOD) δ1.53 (6 H, s), 2.09 (3 H, s), 3.67 (3 H, s), 4.60 (2 H, s). 5.31 (2 H,s), 6.67- 6.86 (3 H, m), 6.97 (1 H, ddd), 7.17- 7.40 (4 H, m). 55 II

2-([5-(3-methoxyphenyl)-1-phenyl- 1H-pyrazol-3-yl]methoxy)-2-methyl-propanoic acid ¹H-NMR (300 MHz, MeOD) δ 1.53 (6 H, s), 3.64 (3 H, s),4.61 (2 H, s), 6.63-6.77 (2 H, m), 6.77-6.93 (2 H, m), 7.16-7.36 (3 H,m), 7.40 (3 H, dddd). 56 II

2-([5-(3-methoxyphenyl)-1-(pyridin- 2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 367 ¹H-NMR (400 MHz, MeOD) δ 1.54(6 H, s), 3.69 (3 H, s), 4.65 (2 H, s), 6.70 (1 H, s), 6.76-6.78 (2 H,m), 6.89(1 H, ddd), 7.20-7.25 (1H, d), 7.41-7.45 (2H, m), 7.91 (1 H,dt), 8.41 (1 H, t). 57 II

2-([1-(2-chlorophenyl)-5-(3- methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 401 ¹H-NMR (400 MHz,MeOD) δ 1.55 (6 H, s), 3.64 (3 H, s), 4.63 (2 H, s), 6.73 (2 H, d), 6.86(2 H, dd), 7.20 (1 H, dd), 7.42-7.60 (4 H, m). 58 II

2-([1-(3-chlorophenyl)-5-(3- methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, MeOD) δ 1.54 (6 H,s), 3.71 (3 H, s), 4.62 (2 H, s), 6.68 (1 H, s), 6.77-6.87 (2 H, m),6.94 (1 H, ddd), 7.19 (1 H, dt), 7.27 (1 H, t), 7.32-7.44 (3 H, m). 59II

2-([1-(4-chlorophenyl)-5-(3- methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 401 ¹H-NMR (400 MHz,MeOD) δ 1.54 (6 H, s), 3.71 (3 H, s), 4.62 (2 H, s), 6.67 (1 H, s),6.75-6.85 (2 H, m), 6.92 (1 H, ddd), 7.21-7.32 (3 H, m), 7.37-7.46 (2 H,m). 60 VII

2-([1-Benzyl-5-[3-(2- methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, MeOD) δ 0.97 (6 H,d), 1.53 (6 H, s), 1.97 (1 H, dp), 3.48 (2 H, d), 3.78 (3 H, s), 4.58 (2H, s), 5.31 (2 H, s), 6.52 (1 H, s), 6.67- 6.74 (1 H, m), 6.76-6.82 (1H, m), 6.85-7.00 (4 H, m), 7.22-7.33 (2 H, m) 61 VII

2-([1-[(2-methoxyphenyl)methyl]-5- [3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid LC-MS (ES, m/z): 453¹H-NMR (400 MHz, MeOD) δ 0.97 (6 H, d), 1.53 (6 H, s), 1.97 (1 H, dp),3.48 (2 H, d), 3.78 (3 H, s), 4.58 (2 H, s), 5.31 (2 H, s), 6.52 (1 H,s), 6.67- 6.74 (1 H, m), 6.76-6.82 (1 H, m), 6.85-7.00 (4 H, m),7.22-7.33 (2 H, m). 62 VII

2-([1-[(3-methoxyphenyl)methyl]-5- [3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid LC-MS (ES, m/z): 453¹H-NMR (400 MHz, MeOD) δ 0.99 (6 H, d), 1.53 (6 H, s), 1.99 (1 H, dq),3.55 (2 H, d), 3.73 (3 H, s), 4.59 (2 H, s), 5.33 (2 H, s), 6.50 (1 H,s), 6.56- 6.65 (2 H, m), 6.78-6.86 (2 H, m), 6.92-7.00 (2 H, m), 7.22 (1H, t), 7.33 (1 H, t). 63 VII

2-([1-[(4-methoxyphenyl)methyl]-5- [3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid LC-MS (ES, m/z): 453¹H-NMR (400 MHz, MeOD) δ 1.00 (6 H, d), 1.53 (6 H, s), 2.01 (1 H, dp),3.57 (2 H, d), 3.77 (3 H, s), 4.58 (2 H, s), 5.29 (2 H, s), 6.47 (1 H,s), 6.78- 6.90 (3 H, m), 6.92-7.01 (4 H, m), 7.29-7.39 (1 H, m). 64 VIII

2-([1-[(2-Chlorophenyl)methyl]-5-(5- methoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (300 MHz, MeOD): δ 1.51 (6 H,s), 3.86 (3 H, s), 4.54 (2 H, s), 5.50 (2 H, s), 6.19 (1 H, d), 6.51 (1H, s), 6.55-6.66 (2 H, m), 7.25 (2 H, dtd), 7.43 (1 H, dd). 65 VIII

2-([1-[(2-Chlorophenyl)methyl]-5-(4- methoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (300 MHz, MeOD): δ 1.51 (6 H,s), 3.76 (3 H, s), 4.56 (2 H, s), 5.54 (2 H, s), 6.51 (1 H, d), 6.56-6.69 (3 H, m), 7.26 (2 H, dtd), 7.44 (1 H, dd). 66 VIII

2-([1-[(2-chlorophenyl)methyl]-5-(5- methoxythien-3-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, MeOD) δ 1.53 (6 H,s), 3.85 (3 H, s), 4.57 (2 H, s), 5.52 (2 H, s), 6.26 (1 H, d), 6.52-6.59 (2 H, m), 6.64-6.71 (1 H, m), 7.28 (2 H, dtd), 7.45 (1 H, dd). 67VII

2-([1-[(2-Chlorophenyl)methyl]-5-(3- methoxyphenyl)-1H-pyrazol-3-yl)methoxy)-2-ethylbutyric acid ¹H-NMR (400 MHz, MeOD): δ (0.91 (6 H,t), 1.87 (4 H, q), 3.68 (3 H, s), 4.52 (2 H, s), 5.43 (2 H, s), 6.67 (1H, s), 6.72-6.86 (2 H, m), 6.88-7.00 (2 H, m), 7.21-7.36 (3 H, m), 7.37-7.48 (1 H, m). 68 VII

2-([1-[(2-Chlorophenyl)methyl]-5-(3- methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid ¹H-NMR (400 MHz, MeOD) δ 0.97 (3 H,t), 1.51 (3 H, s), 1.89 (2 H, qd), 3.68 (3 H, s), 4.59 (2 H, s), 5.44 (2H, s), 6.56 (1 H, s), 6.71-6.79 (1 H, m), 6.83 (1 H, dd), 6.89-7.01 (2H, m), 7.22-7.36 (3 H, m), 7.37-7.45 (1 H, m). 69 XVIII

2-([1-[(2-Chlorophenyl)methyl]-5-[3- (2-methylpropanamido)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H-NMR (300 MHz, DMSO): δ1.09 (6 H, d), 1.39 (6 H, s), 2.57 (1 H, p), 5.39 (2 H, s), 6.40 (1 H,s), 6.69- 6.79 (1 H, m), 7.00 (1 H, dt), 7.21- 7.48 (4 H, m), 7.53-7.63(1 H, m), 7.78(1 H, t), 9.93(1 H, s). 70 XIX

2-([1-[(2-Chlorophenyl)methyl]-5-(3- methanesulfonylphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, MeOD): δ 1.54 (6H, s), 3.10 (3 H, s), 4.61 (2 H, s), 5.48 (2 H, s), 6.67 (1 H, s), 6.82(1 H, dd), 7.21-7.33 (2 H, m), 7.35-7.42 (1 H, m), 7.64-7.74 (2 H, m),7.90 (1 H, q), 7.96-8.03 (1 H, m). 71 XIX

2-([1-[(2-Chlorophenyl)methyl]-5-(3- methanesulfonamidophenyl)-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoic acid ¹H-NMR (300 MHz, MeOD): δ1.52 (6 H, s), 2.04 (1 H, s), 2.87 (3 H, s), 4.58 (2 H, s), 5.44 (2 H,s), 6.56 (1 H, s), 6.66-6.76 (1 H, m), 7.12 (1 H, dt), 7.25 (4 H, dtd),7.32-7.44 (2 H, m). 72 XIX

2-([1-[(2-chlorophenyl)methyl]-5-[3- (methylamino)phenyl]-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid ¹H-NMR (300 MHz, MeOD): δ 1.52 (6 H,s), 2.04 (1 H, s), 2.87 (3 H, s), 4.58 (2 H, s), 5.44 (2 H, s), 6.56 (1H, s), 6.66-6.76 (1 H, m), 7.12 (1 H, dt), 7.25 (4 H, dtd), 7.32-7.44 (2H, m). 73 XIX

2-([1-[(2-chlorophenyl)methyl]-5-[3- [(2-methylpropyl)amino]phenyl]-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoic acid ¹H-NMR (300 MHz, MeOD): δ0.88 (6 H, d), 1.52 (6 H, s), 1.74 (1 H, dp), 2.66 (2 H, d), 4.57 (2 H,s), 5.42 (2 H, s), 6.40-6.77 (5 H, m), 7.11 (1 H, dd), 7.19-7.35 (2 H,m), 7.35-7.47 (1 H, m). 74 XII

2-([1-[(2-Chlorophenyl)methyl]-5-[3- [(propan-2-yl)carbamoyl]phenyl]-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoic acid ¹H-NMR: (400 MHz,DMSO-d₆) δ 1.16 (6 H, d), 1.41 (6 H, s), 3.33 (5 H, s), 4.02-4.17 (1 H,m), 4.44 (2 H, s), 5.40 (2 H, s), 6.53(1 H, s), 6.75- 6.88 (1 H, m),7.23-7.36 (2 H, m), 7.41-7.47 (1 H, m), 7.49-7.57 (2 H, m), 7.81-7.98 (2H, m), 8.29 (1 H, d), 12.63 (1 H, s).

Example 75:2-([1-[(2-chlorophenyl)methyl]-5-(phenylamino)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

2-[(5-[[(tert-Butoxy)carbonyl](phenyl)amino]-1-[(2-chlorophenyl)methyl]-1H-pyrazol-3-yl)methoxy)-2-methylpropanoicacid was prepared from Int. H-93 using the procedure of Example 1. Thisresulted in 200 mg as yellow oil.

2-([1-[(2-Chlorophenyl)methyl]-5-(phenylamino)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

To a solution of the product from the previous step (200 g, 400.01 mmol,1.00 equiv) in DCM (10 mL) was added TFA (5 mL) dropwise with stirringat rt. The resulting solution was stirred for 1 h, then concentratedunder vacuum. The crude product (150 mg) was purified by Prep-HPLC withthe following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column,SunFire C18 OBD Prep Column, 0.1 nM, 5 uM, 19 mm×150 mm, mobile phase,Waters (0.1% TFA) and ACN (61.0% ACN up to 74.0% in 6 min); Detector, UV254 nm), to afford 19.2 mg of the title product as a white solid.

¹H-NMR (300 MHz, MeOD) δ 1.50 (6H, s), 4.48 (2H, s), 5.34 (2H, d), 6.18(1H, s), 6.68-6.95 (4H, m), 7.11-7.30 (4H, m), 7.33-7.43 (1H, m).

The following Examples were prepared using the indicated Schemes.

TABLE 21 Examples 76-77. IUPAC Name Ex. Scheme Structure Analytical data76 XVII

2-([1-[(2-Chlorophenyl)methyl]-5- phenoxy-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (CD3OD, ppm): δ (300 MHz, MeOD) 1.46 (6 H,s), 4.44 (2 H, s), 5.35 (2 H, s), 5.78 (1 H, s), 6.90-7.00 (1 H, m),7.06-7.46 (8 H, m). 77 VI

2-([5-Benzyl-1-[(2-chlorophenyl)- methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (300 MHz, MeOD): δ 1.48 (6 H, s), 3.92 (2H, s), 4.50 (2 H, s), 5.32 (2 H, s), 6.23 (1 H, s), 6.42- 6.52 (1 H, m),7.07-7.30 (7 H, m), 7.39 (1 H, dd).

Example 78 is intentionally left blank.

Example 79:2-([1-[(2-Chlorophenyl)methyl]-5-(3-hydroxyphenyl)1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

(i)2-([1-[(2-Chlorophenyl)methyl]-5-(3-hydroxyphenyl)1H-pyrazol-3-yl]methoxy)-2-methylpropanoicacid: A solution of methyl2-([5-(3-benzyloxyphenyl)-1-[(2-chlorophenyl)-methyl]1H-pyrazol-3-yl]methoxy)-2-methyl-propanoatein mixture of acetic acid and conc HCl (8 mL) (3:1, v/v) was heated at90° C. for 6 h. At the end of this period the reaction mixture wasevaporated to dryness and the residue was chromatographed over SiO₂using 0-20% gradient of MeOH in DCM to afford the title product. ¹HNMR(CDCl₃): δ 1.55 (s, 6H), 4.61 (s, 2H), 5.40 (s, 2H), 6.38 (s, 1H),6.74-6.83 (m, 4H), 7.18-7.35 (m, 4H).

Example 80:2-([1-[(2-Chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

(i) Methyl2-([1-[(2-chlorophenyl)methyl]-5-(3-hydroxyphenyl)1H-pyrazol-3-yl]-methoxy)-2-methyl-propanoate

To a solution of 2-([1-[(2-chlorophenyl)methyl]-5-(3-hydroxy-phenyl)1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid (Example 79) in MeOH wasadded 4 drops of conc H₂SO₄, and the solution was refluxed for 16 h. Theproduct was evaporated to dryness and the residue was chromatographedover SiO₂ using 0-25% gradient of MeOH in DCM to afford the titleproduct.

(ii) Methyl2-([1-[(2-chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]1H-pyrazol-3-yl]methoxy)-2-methyl-propanoate

To a solution of methyl2-([1-[(2-chlorophenyl)-methyl]-5-(3-hydroxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methyl-propanoate(0.170 g, 0.410 mmol) in DMF was added [oxetan-3-yl]methyl4-methylbenzenesulfonate (0.149 g, 0.615 mmol) and K₂CO₃ (0.113 g, 0.820mmol) at room temperature. The mixture was heated at 60° C. for 16 h.The reaction mixture was cooled to room temperature, water was added,and the mixture was extracted with EtOAc (20 mL×2). The combined organiclayers were washed with water (20 mL) and brine (20 mL), dried overNa₂SO₄, and concentrated under reduced pressure. The residue waschromatographed over SiO₂ using 0-100% gradient of EtOAc in hexane toafford the title product. ¹HNMR (CDCl₃): δ 1.54 (s, 6H), 3.33-3.36 (m,1H), 3.77 (s, 3H), 3.97 (d, 2H), 4.30 (t, 2H), 4.56 (s, 2H), 4.84 (t,2H), 5.40 (s, 2H), 6.53 (s, 1H), 6.77-6.90 (m, 4H), 7.19-7.37 (m, 4H).

(iii)2-([1-[(2-Chlorophenyl)methyl]-5-[3-(oxetan-3-ylmethoxy)phenyl]1H-pyrazol-3-yl]methoxy)-2-methylpropanoicacid was prepared analogously as described in Step iv of Example 1,yielding the title product (20 mg). ¹HNMR (CDCl₃): δ 1.55 (s, 6H),3.34-3.74 (m, 1H), 3.98 (d, 2H), 4.49 (t, 2H), 4.63 (s, 2H), 4.83 (t,2H), 5.43 (s, 2H), 6.44 (s, 1H), 6.76-6.93 (m, 4H), 7.20-7.37 (m, 4H).

Example 81:2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)1H-pyrazol-3-yl]methoxy)-2-methyl-N-methylsulfonyl-propanamide

To a solution of Example 14(2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicacid) (0.08 g, 0.192 mmol) in CH3CN was added CDI (0.047 g, 0.288 mmol)and methanesulfonamide (0.022 g, 0.23 mmol) at rt. The mixture wasstirred at rt for 16 h. The solvent was evaporated and the residue waschromatographed over SiO₂ using 0-20% gradient of MeOH in DCM to affordthe title product. ¹HNMR (CDCl₃): δ 1.55 (s, 6H), 3.21 (s, 3H), 3.67 (s,3H), 4.58 (s, 2H), 5.48 (s, 2H), 6.36 (s, 1H), 6.75-6.92 (m, 4H),7.18-7.35 (m, 4H).

Example 82: Methyl2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)1H-pyrazol-3-yl]methoxy)-2-methyl-propanoate

Example 82 was prepared analogously as described in Example 1, omittingStep iv. ¹HNMR (CDCl₃): δ1.54 (s, 6H), 3.65 (s, 3H), 3.77 (s, 3H), 4.56(s, 2H), 5.37 (s, 2H), 6.53 (s, 1H), 6.71-6.78 (m, 2H), 6.85-6.90 (m2H), 7.10-7.13 (m, 1H), 7.21-7.27 (m, 2H), 7.51-7.53 (m 1H).

Examples 83-100 are intentionally left blank.

The following Examples were prepared using the indicated Schemes.

TABLE 22 Examples 101-119. IUPAC Name Ex. Scheme Structure Analyticaldata 101 II

2-([1-(2-Chlorophenyl)-5-[3-(2- methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 443. ¹H-NMR (400MHz, DMSO) δ 0.90 (6 H, d), 1.25 (1 H, d), 1.43 (6 H, s), 1.88(1 H,hept), 3.54 (2 H, d), 4.48 (2 H, s), 6.65-6.73 (2 H, m), 6.75- 6.88 (2H, m), 7.20 (1 H, t), 7.45- 7.65 (4 H, m). 102 II

2-([l-(2-Methoxyphenyl)-5-[3-(2- methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 439 ¹H-NMR (400MHz, DMSO) δ 0.90 (6 H, d), 1.43 (6 H, s), 1.87 (1 H, hept), 3.45-3.55(5 H, m), 4.45 (2 H, s), 6.60 (1 H, s), 6.67 (1 H, dd), 6.76-6.86 (2 H,m), 7.01-7.23 (3 H, m), 7.35 (1 H, dd), 7.44 (1 H, ddd), 12.73 (1 H, s).LC-MS (ES, m/z): 439. 103 II

2-([1-[2-(Dimethylamino)phenyl]-5- [3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid. LC-MS (ES, m/z): 452¹H-NMR (300 MHz, MeOD) δ 1.02 (6 H, d), 1.53 (6 H, s), 2.04 (1 H, dt),3.02 (6 H, s), 3.65 (2 H, d), 4.60 (2 H, s), 5.48 (2 H, s), 6.49 (1 H,s), 6.81 (1 H, d), 6.92-7.05 (3 H, m), 7.26 (1 H, t), 7.42 (2 H, dt),7.54 (1H, d). 104 II

2-methyl-2-([5-[3-(2- methylpropoxy)phenyl]-1-phenyl-1H-pyrazol-3-yl]methoxy)propanoic acid LC-MS (ES, m/z): 409 1H-NMR (300MHz, MeOD) 7.48- 7.32 (m, 3H), 7.35-7.14 (m, 3H), 6.91-6.78 (m, 2H),6.73-6.63 (m, 2H), 4.61 (s, 2H), 3.54 (d, J = 6.5 Hz, 2H), 1.92 (hept, J= 6.7 Hz, 1H), 1.53 (s, 6H), 0.95 (d, J = 6.7 Hz, 6H). 105 II

2-Methyl-2-([1-(2-methylphenyl)-5- [3-(2-methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy]propanoic acid. LC-MS (ES, m/z): 423 ¹H-NMR (300MHz, MeOD) δ 0.95 (d, 6H), 1.54 (s, 6H), 1.81-2.01 (m, 4H), 3.34 (s,1H), 3.46 (d, 2H), 4.61 (s, 2H), 6.63 (dd, 1H), 6.71-6.92 (m, 3H), 7.18(t, 1H), 7.26-7.47 (m, 4H). 106 II

2-([1-(2-fluorophenyl)-5-[3-(2- methylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 427 1H-NMR (300MHz, MeOD) δ 7.57- 7.46 (m, 2H), 7.38-7.29 (m, 1H), 7.28-7.16 (m, 2H),6.91-6.81 (m, 2H), 6.72 (q, 2H), 4.63 (s, 2H), 3.56 (d, 2H), 1.98-1.93(m, 1H), 1.55 (s, 6H), 0.98 (d, 6H). 107 XIII

2-[(1-[[4- (Dimethylamino)phenyl]methyl]-5-[3-(2-methylpropoxy)phenyl]-1H- pyrazol-3-yl)methoxy)-2- methylpropanoicacid ¹H-NMR (400 MHz, DMSO) δ 0.95 (7 H, d), 1.21-1.27 (1 H, m), 1.40 (6H, s), 1.96 (1 H, dq), 2.84 (6 H, s), 3.64 (2 H, d), 4.40 (2 H, s), 5.18(2 H, s), 6.37 (1 H, s), 6.60-6.67 (2 H, m), 6.83-6.92 (3 H, m), 6.98 (2H, ddd), 7.36 (1 H, 1), 12.68 (1 H, s). LC-MS (ES, m/z): 466. 108 XIII

2-[(1-[[3-(Dimethylamino)phenyl]- methyl]-5-[3-(2-methylpropoxy)-phenyl]-1H-pyrazol-3-yl)methoxy)-2- methylpropanoic acid. LC-MS (ES,m/z): 466 ¹H-NMR (300 MHz, MeOD) δ 1.01 (6 H, d), 1.54 (6 H, s),1.95-2.06 (1 H, m), 3.07 (6 H, s), 3.56 (2 H, d), 4.59 (2 H, s), 5.32 (2H, s), 6.51 (1 H, s), 6.80-6.87 (3 H, m), 7.10 (2 H, d), 7.24 (1 H,ddd), 7.32-7.37 (2 H, dd). 109 XIII

2-[(1-[[2-(Dimethylamino)phenyl]- methyl]-5-[3-(2-methylpropoxy)-phenyl]-1H-pyrazol-3-yl)methoxy)-2- methylpropanoic acid. LC-MS (ES,m/z): 466 ¹H-NMR (300 MHz, MeOD) δ 1.02 (6 H, d), 1.53 (6 H, s), 2.04 (1H, dt), 3.02 (6 H, s), 3.65 (2 H, d), 4.60 (2 H, s), 5.48 (2 H, s), 6.49(1 H, s), 6.81 (1 H, d), 6.92-7.05 (3 H, m), 7.26 (1 H, t), 7.42 (2 H,dt), 7.54 (1H, d). 110 VII

2-([1-(2-Chlorophenyl)-5-(3-cyclo- propoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H NMR (MeOD, ppm): δ: 0.50- 0.59 (m,2H), 0.63-0.72 (m, 2H), 1.55 (s, 6H), 3.53 (tt, 1H), 4.63 (s, 2H), 6.73(s, 1H), 6.86-6.98 (m, 3H), 7.22 (t, 1H), 7.41-7.61 (m, 4H). LC-MS (ES,m/z): 427. 111 VII

2-([5-(3-Cyclopropoxyphenyl)-1-[(2- methoxyphenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 437 ¹H-NMR (300MHz, CDCl₃) δ 0.54- 0.61 (2 H, m), 0.65 (2 H, dt), 1.53 (6 H, s),3.45-3.58 (1 H, m), 3.74 (3 H, s), 4.63 (2 H, s), 5.38 (2 H, s), 6.41 (1H, s), 6.76-6.84 (2 H, m), 6.85- 6.92 (1 H, m), 7.01 (2 H, dd), 7.17-7.35 (3 H, m). 112 VII

2-([5-(3-cyclopropoxyphenyl)-1-(2- methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 423 ¹H NMR (300 MHz,MeOD) δ 7.45 (ddd, J = 8.3, 7.5, 1.7 Hz, 1H), 7.38 (dd, J = 8.0, 1.7 Hz,1H), 7.19 (ddd, J = 7.6, 6.9, 2.0 Hz, 1H), 7.07 (m, 2H), 6.90 (m, 3H),6.65 (s, 1H), 4.60 (s, 2H), 3.51 (m, 4H), 1.53 (s, 6H), 0.63 (m, 2H),0.54 (m, 2H). 113 VII

2-([1-(2-Methoxyphenyl)-5-[3- (propan-2-yloxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 425 ¹H-NMR (300MHz, MeOD) δ 1.16 (6 H, d), 1.53 (6 H, s), 3.53 (3 H, s), 4.30 (1 H, p),4.59 (2 H, s), 6.64 (1 H, s), 6.67-6.72 (1 H, m), 6.79 (1 H, ddd), 6.86(1 H, dt), 7.01-7.10 (2 H, m), 7.17 (1 H, t), 7.34-7.39 (1 H, m), 7.43(1 H, td). 114 VII

2-([5-(3-cyclopropoxyphenyl)-1-[2- (dimethylamino)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 436 1H-NMR (300MHz, CDCl3) δ 7.47- 7.29 (m, 2H), 7.26-7.06 (m, 3H), 6.96-6.81 (m, 3H),6.71 (s, 1H), 4.63 (s, 2H), 3.50 (tt, J = 6.2, 3.0 Hz, 1H), 2.44 (s,6H), 1.54 (s, 6H), 0.70- 0.47 (m, 4H). 115 II

2-([5-(3-Methoxyphenyl)-1-(pyridin- 3-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, MeOD) δ 1.55 (s, 6H), 3.72 (s,3H), 4.65 (s, 2H), 6.73 (s, 1H), 6.79-6.88 (m, 2H), 6.96 (ddd, J = 8.4.2.5, 0.9 Hz, 1H), 7.25-7.34 (m, 1H), 7.51 (dd, J = 8.3, 4.8 Hz, 1H),7.82 (ddd, J = 8.3, 2.5, 1.4 Hz, 1H), 8.49 (d, J = 2.5 Hz, 1H), 8.53(dd, J = 4.9, 1.4 Hz, 1H). LC- MS (ES, m/z): 368. 116 II

2-([5-(3-Methoxyphenyl)-1-(pyridin- 3-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 368. ¹H-NMR (400 MHz, DMSO) δ2.23 (s, 5H), 4.53 (s, 3H), 5.31 (s, 2H), 7.49 (s, 1H), 7.63 (d, 1H),7.22 (t, 1H), 7.72 (s, 1H), 7.81-7.83 (m, 1H), 8.07-8.09 (m, 2H),8.12-8.16 (m, 1H), 9.38 (d, 2H). 117 II

2-([1-(2-Fluorophenyl)-5-(3- methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 384 ¹H-NMR (300MHz, MeOD) δ 1.55 (6 H, d), 3.66 (3H, s), 4.63 (2 H, s), 6.72 (1 H, s),6.75 (1 H, dd), 6.81- 6.92 (2 H, m), 7.17-7.28 (2 H, m), 7.28-7.37 (1 H,m), 7.46-7.56 (2H, m). 118 II

2-([5-(3-methoxyphenyl)-1-(2- methylphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 381 1H-NMR (300MHz, MeOD) δ 7.49- 7.28 (m, 4H), 7.18 (t, 1H), 6.94- 6.79 (m, 2H), 6.74(s, 1H), 6.67 (dd, 1H), 4.61 (s, 2H), 3.59 119 II

22-([1-(2-Methoxyphenyl)-5-(3- methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 397 ¹H-NMR (300MHz, CDCl₃) δ 1.57 (6 H, s), 3.48 (3 H, s), 3.62 (3 H, s), 4.68 (2 H,s), 6.57 (1 H, s), 6.72 (1 H, dd), 6.76-6.85 (2 H, m), 6.88 (1 H, dd),7.01 (1 H, td), 7.15 (1 H, t), 7.31- 7.36 (1 H, m), 7.37-7.44 (1 H, m).

Examples 120/121:(2S)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoicacid and(2R)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoicAcid

Ethyl2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate

To a solution of Int. G-1 (700 mg, 1.79 mmol, 1.00 equiv) in THF (10mL), under N₂, was added NaH (200 mg, 8.33 mmol, 3.00 equiv). Thesolution was stirred for 10 min at 0° C. To this was added methyl2-hydroxy-2-methylbutanoate (700 mg, 5.30 mmol, 3.00 equiv), Bu₄NI (330mg, 0.50 equiv). The resulting solution was stirred for 4 h at roomtemperature. The reaction was quenched by the addition of 1 mL of water.The resulting solution was diluted with 20 mL of H₂O, extracted with2×30 mL of EtOAc, and the organic layers were combined. The resultingmixture was washed with 20 mL of saturated NaCl, then dried overanhydrous Na₂SO₄ and concentrated under vacuum. The residue was appliedonto a silica gel column with EtOAc/petroleum ether (1:5). This resultedin the title compound as a yellow oil (300 mg, 38%).

(vi) Chiral separation of Ethyl2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate

The crude product of step v was purified by Chiral-Prep-HPLC with thefollowing conditions (Prep-HPLC-004): Column, Chiralpak IC, 2*25 cm,Sum; mobile phase, Hex- and ethanol- (hold 2.0% ethanol- in 23 min);Detector, UV 254/220 nm. 100 mg product was obtained which Alpha(25° C.,0.05 mol/L, MeOH). This resulted in ethyl(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoateas colorless oil (100 mg, 36%) and ethyl(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoateas colorless oil (100 mg, 36%).

(vii)(2S)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoicacid was obtained from ethyl(2S)-2-([1-[(2-chlorophenyl)-methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoateanalogously as described in Step iv of Example 1. ¹H-NMR (400 MHz, MeOD)δ 7.45-7.38 (m, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.31-7.29 (m, 1H),7.29-7.24 (m, 1H), 6.83 (dd, J=2.5, 1.6 Hz, 1H), 6.80-6.72 (m, 1H), 6.56(s, 1H), 5.44 (s, 2H), 4.59 (s, 2H), 3.69 (s, 3H), 1.89 (qd, J=7.2, 5.0Hz, 2H), 1.51 (s, 3H), 0.98 (t, J=7.5 Hz, 3H).LC-MS (ES, m/z): 429.

(viii)(2R)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoicacid was obtained from ethyl(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoateanalogously as described in Step iv of Example 1. ¹H-NMR (400 MHz, MeOD)δ 7.45-7.38 (m, 1H), 7.37-7.31 (m, 1H), 7.31-7.29 (m, 1H), 7.29-7.24 (m,1H), 6.97 (ddd, J=8.4, 2.6, 0.9 Hz, 1H), 6.93 (dt, J=7.6, 1.2 Hz, 1H),6.83 (dd, J=2.6, 1.6 Hz, 1H), 6.81-6.72 (m, 1H), 6.56 (s, 1H), 5.44 (s,2H), 4.59 (s, 2H), 3.69 (s, 3H), 1.89 (qd, J=7.2, 4.9 Hz, 2H), 1.51 (s,3H), 0.98 (t, J=7.5 Hz, 3H). LC-MS (ES, m/z): 429.

Alternative Synthesis of Examples 120/121:(2S)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoicacid and(2R)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoicAcid

Methyl2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate

To a solution of methyl 2-hydroxy-2-methylbutanoate (780 mg, 5.90 mmol,1.00 equiv) in THF (50 mL) under N₂ was added NaH (236 mg, 5.90 mmol,1.00 equiv) in portions at 0° C. The mixture was stirred at 0° C. for 30min, then Int. G-1 (1.16 g, 2.96 mmol, 0.50 equiv) and Bu₄NI (600 mg,1.63 mmol, 0.50 equiv) were added at 0° C. The resulting solution wasstirred for 16 h at rt, then quenched by the addition of water/ice. Theresulting solution was diluted with 200 mL of EtOAc, washed with 2×100mL of brine, dried over Na₂SO₄, concentrated under vacuum, and purifiedby Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Prep OBD C18 Column,30??150 mm 5 um; mobile phase, Water (0.1% FA) and ACN (55.0% ACN up to79.0% in 7 min); Detector, UV 254/220 nm, to afford 200 mg (8%) of thetitle compound as a colorless oil. LC-MS: (ES, m/z): 443.

Chiral Separation of (2R)- and (2S)-Methyl2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate

The racemic methyl ester (200 mg, 0.45 mmol, 1.00 equiv) was separatedinto enantiomers by Chiral-Prep-HPLC with the following conditionsColumn: Chiralpak IC, 2*25 cm, 5 um; Mobile Phase A:Hex—HPLC, MobilePhase B: EtOH—HPLC; Flow rate: 20 mL/min; Gradient: 2 B to 2 B in 24min; 220/254 nm; RT1:18.171; RT2:20.742, affording 80 mg (40%) of methyl(2S)-2-([1-[(2-chlorophenyl)-methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate,and 70 mg (35%) of methyl(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate,both as colorless oils.

Alternate Synthesis of methyl(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate

Methyl(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate

To a solution of methyl (2S)-2-hydroxy-2-methylbutanoate (400 mg, 3.03mmol, 1.00 equiv) in THF (20 mL) was added NaH (122 mg, 3.05 mmol, 1.00equiv) in portions at 0° C. The mixture was stirred at 0° C. for 10 min,then Int. G-1 (400 mg, 1.02 mmol, 0.34 equiv) and Bu₄NI (200 mg, 0.54mmol, 0.50 equiv) were added at 0° C. The resulting solution was stirredfor 16 h at rt, quenched by the addition of water/ice, and extractedwith 100 mL of EtOAc. The combined organic layers were washed with 1×100mL of brine, dried over Na₂SO₄, concentrated under vacuum, and purifiedwith Prep-TLC using EtOAc/petroleum ether (1:3) to afford 150 mg (11%)of the title compound as a colorless oil. LC-MS: (ES, m/z): 443.

Example 120.(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoicAcid

To a solution of methyl(2S)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate(70 mg, 0.16 mmol, 1.00 equiv) in THF/H₂O/MeOH (4/2/2 mL) was added LiOH(23 mg, 0.96 mmol, 6.00 equiv), in portions at rt. The resultingsolution was stirred for 2 h at room temperature. The pH v was adjustedto 3-4 with conc HCl. The resulting solution was extracted with 100 mLof EtOAc. The combined organic layers were dried over Na₂SO₄,concentrated under vacuum, and purified by Prep-HPLC with the followingconditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Prep OBDC18 Column, 30??150 mm 5 um; mobile phase, Water (0.1% FA) and ACN(40.0% ACN up to 75.0% in 7 min); Detector, UV 254/220 nm to afford 40mg (59%) of the title compound as a colorless oil. LC-MS: (ES, m/z):429. ¹H NMR: (400 MHz, DMSO-d₆) δ12.60 (s, 1H), 7.50-7.22 (m, 4H),7.02-6.84 (m, 3H), 6.78-6.69 (m, 1H), 6.45 (s, 1H), 5.38 (s, 2H), 4.41(d, J=2.2 Hz, 2H), 3.69 (s, 3H), 1.87-1.61 (m, J=7.1 Hz, 2H), 1.36 (s,3H), 0.85 (t, J=7.4 Hz, 3H).

Example 121.(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoicAcid

To a solution of methyl(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoate(80 mg, 0.18 mmol, 1.00 equiv) in THF/H₂O/MeOH (4/2/2 mL) was added LiOH(26 mg, 1.09 mmol, 6.00 equiv) in portions at rt. The resulting solutionwas stirred for 2 h at rt. The pH value was adjusted to 3-4 with conHCl.The resulting solution was extracted with 100 mL of EtOAc, and theorganic layers were combined, dried over Na₂SO₄, concentrated undervacuum, and purified by Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Prep OBD C18 Column,30??150 mm Sum; mobile phase, Water (0.1% FA) and ACN (40.0% ACN up to75.0% in 7 min); Detector, UV 254/220 nm to afford 46.3 mg (60%) of thetitle compound as a colorless oil. LC-MS: (ES, m/z): 429. ¹H NMR: (400MHz, DMSO-d₆) δ12.61 (s, 1H), 7.49-7.22 (m, 4H), 7.02-6.84 (m, 3H),6.78-6.69 (m, 1H), 6.46 (s, 1H), 5.38 (s, 2H), 4.41 (d, J=2.2 Hz, 2H),3.69 (s, 3H), 1.84-1.61 (m, J=7.6 Hz, 2H), 1.36 (s, 3H), 0.85 (t, J=7.4Hz, 3H).

The following Examples were prepared using Scheme III.

TABLE 23 Examples 122-127. IUPAC Name Ex. Structure Analytical data 122

(2S)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)- butanoic acid. LC-MS (ES, m/z):415. ¹H-NMR (400 MHz, MeOD) δ 7.46-7.37 (m, 1H), 7.36-7.21 (m, 3H),7.00-6.88 (m, 2H), 6.82 (dd, J = 2.6, 1.5 Hz, 1H), 6.79-6.71 (m, 1H),6.58 (s, 1H), 5.44 (s, 2H), 4.76 (d, J = 12.1 Hz, 1H), 4.47 (d, J = 12.1Hz, 1H), 3.82 (dd, J = 7.3, 4.7 Hz, 1H), 3.68 (s, 3H), 1.89- 1.66 (m,2H), 1.00 (t, J = 7.4 Hz, 3H). 123

(2R)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)- butanoic acid. LC-MS (ES, m/z):415 ¹H-NMR (300 MHz, MeOD) δ 7.46-7.36 (m, 1H), 7.36-7.22 (m, 3H),7.00-6.88 (m, 2H), 6.82 (dd, J = 2.6, 1.5 Hz, 1H), 6.78-6.71 (m, 1H),6.58 (s, 1H), 5.44 (s, 2H), 4.75 (d, J = 12.1 Hz, 1H), 4.46 (d, J = 12.1Hz, 1H), 3.82 (dd, J = 7.4, 4.8 Hz, 1H), 3.68 (s, 3H), 1.90- 1.66 (m,2H), 1.00 (t. J = 7.4 Hz, 3H). 124

(2S)-2-([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)- propanoic acid LC-MS (ES, m/z):401 ¹H-NMR (300 MHz, MeOD) δ 7.49-7.36 (m, 1H), 7.34-7.22 (m, 3H),7.01-6.89 (m, 2H), 6.83 (dd, J = 2.6, 1.6 Hz, 1H), 6.79-6.71 (m, 1H),6.55 (s, 1H), 5.45 (s, 2H), 4.73 (d, J = 11.9 Hz, 1H), 4.56 (d, J = 11.9Hz, 1H), 4.17 (q, J = 6.9 Hz, 1H), 3.68 (s, 3H), 1.44 (d, J = 6.9 Hz,3H). 125

(2R)-2-([1-((2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)- propanoic acid. LC-MS (ES,m/z): 401 ¹H-NMR (300 MHz, MeOD) δ 7.45-7.37 (m, 1H), 7.37-7.22 (m, 3H),7.01-6.89 (m, 2H), 6.83 (dd, J = 2.6, 1.6 Hz, 1H), 6.79-6.71 (m, 1H),6.56 (s, 1H), 5.45 (s, 2H), 4.73 (d, J = 11.9 Hz, 1H), 4.56 (d, J = 11.9Hz, 1H), 4.17 (q, J = 6.9 Hz, 1H), 3.69 (s, 3H), 1.44 (d, J = 6.8 Hz,3H). 126

2-([1-[(2-Chlorophenyl)methyl]-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H-NMR(300 MHz, MeOD) δ 1.52 (6 H, s), 3.64 (3 H, s), 4.57 (2 H, s), 5.24 (2H, s), 6.40 (1 H, s), 6.73-6.83 (1 H, m), 6.89-7.10 (2 H, m), 7.12-7.24(3 H. m), 7.25-7.46 (2 H, m). LC-MS (ES, m/z): 415. 127

2-([1-[(2-Chlorophenyl)methyl]-5-(4-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid. ¹H-NMR(400 MHz, MeOD) δ 7.44-7.37 (m, 1H), 7.35-7.07 (m, 4H), 7.03-6.89 (m,2H), 6.73 (dd, J = 7.1, 2.1 Hz, 1H), 6.50 (s, 1H), 5.41 (s, 2H), 4.58(s, 2H), 3.82 (s, 3H), 1.53 (s, 6H). LC-MS (ES, m/z): 415.

The following Examples were prepared using the indicated Schemes.

TABLE 24 Examples 128-142. IUPAC Name Ex. Scheme Structure Analyticaldata 128 VIII

2-([1-[(2-Chlorophenyl)methyl]-5-[5- (2-methylpropoxy)thien-2-yl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H-NMR (400 MHz, MeOD) δ1.01 (dd, 6H), 1.52 (s, 6H), 2.07 (ddd, H), 3.83 (dd, 2H), 4.55 (s, 2H),5.52 (s, 2H), 6.17-6.23 (m, 1H), 6.53 (s, 1H), 6.58-6.66 (m, 2H),7.20-7.35 (m, 2H), 7.45 (dt, 1H). LC-MS (ES, m/z): 463. 129 VIII

2-([1-[(2-Chlorophenyl)methyl]-5-[5- (propan-2-yloxy)thien-2-yl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H-NMR (400 MHz, DMSO) δ1.34 (d, 6H), 1.52 (s, 6H), 4.42 (p, 1H), 4.56 (s, 2H), 5.52 (s, 2H),6.22 (dd, 1H), 6.53 (s, 1H), 6.59-6.67 (m, 2H), 7.19-7.35 (m, 2H), 7.45(dd, 1H). LC-MS (ES, m/z): 449. 130 IX

2-([1-[(2-Chlorophenyl)methyl]-5-(4- cyclopropoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, DMSO) δ 1.52 (s,6H), 1.74-1.90 (m, 2H), 2.65 (t, 2H), 4.45 (t, 1H), 4.58 (s, 2H), 5.55(s, 2H), 6.61-6.69 (m, 2H), 6.90 (d, 1H), 7.13 (d, 1H), 7.20-7.38 (m,3H), 7.45 (dd, 1H). LC-MS (ES, m/z): 447. 131 IX

2-([1-[(2-Chlorophenyl)methyl]-5-(5- cyclopropoxythien-2-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, MeOD) δ 1.53 (s,6H), 1.89 (qd, 2H), 2.89 (t, 2H), 4.51 (t, 1H), 4.58 (s, 2H), 5.55 (s,2H), 6.62 (d, 2H), 6.76-6.88 (m, 2H), 7.27 (dt, 2H), 7.45 (dd, 1H). LC-MS (ES, m/z): 447. 132 VIII

2-([1-[(2-Chlorophenyl)methyl]-5-[2-(2-methylpropoxy)-1,3-thiazol-5-yl]- 1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, DMSO) δ 7.46 (dd, J = 7.9, 1.3 Hz,1H), 7.32 (td, J = 7.7, 1.7 Hz, 1H), 7.25 (td, J = 7.6, 1.4 Hz, 1H),7.04 (s, 1H), 6.68-6.60 (m, 2H), 5.52 (s, 2H), 4.57 (s, 2H), 4.18 (d, J= 6.6 Hz, 2H), 2.12 (hept, J = 6.7 Hz, H), 1.52 (s, 6H), 1.33 (dd, J =17.9, 3.5 Hz, 1H), 1.02 (d, J = 6.7 Hz, 6H). LC-MS (ES, m/z): 464. 133VIII

2-([1-[(2-Chlorophenyl)methyl]-5-[2- (propan-2-yloxy)-1,3-thiazol-5-yl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H-NMR (400 MHz, DMSO)δ 7.46 (dd, J = 7.9, 1.4 Hz, 1H), 7.31 (td, J = 7.7, 1.7 Hz, 1H), 7.25(td, J = 7.5, 1.4 Hz, 1H), 7.03 (s, 1H), 6.64 (dd, J = 7.6, 1.7 Hz, 1H),6.61 (s, 1H), 5.52 (s, 2H), 5.13 (dq, J = 12.3, 6.2 Hz, 1H), 4.57 (s,2H), 1.52 (s, 6H), 1.40 (d, J = 6.2 Hz, 6H). LC-MS (ES, m/z): 450. 134 X

2-([1-[(2-Chlorophenyl)methyl]-5-[2- (2-methylpropyl)-1,3-oxazol-5-yl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H-NMR (400 MHz, MeOD)7.46 (dd, J = 7.9, 1.3 Hz, 1H), 7.29 (td, J = 7.5, 1.6 Hz, 1H),7.25-7.18 (m, 1H), 7.17 (s, 1H), 6.81 (s, 1H), 6.59 (dd, J = 7.7, 1.6Hz, 1H), 5.65 (s, 2H), 4.59 (s, 2H), 2.64 (d, J = 7.2 Hz, 2H), 2.09-1.93 (m, 1H), 1.53 (s, 6H), 0.88 (d, J = 6.7 Hz, 6H). LC-MS (ES, m/z):442 135 XI

2-([1-[(2,6- Dimethoxyphenyl)methyl]-5-[3-(2-methylpropoxy)phenyl]1H-pyrazol- 3-yl]methoxy)-2-methylpropanoic acid¹H-NMR (400 MHz, DMSO) δ 0.98 (6 H, d), 1.44 (6 H, s), 2.01 (1 H, dt),3.16 (1 H, s), 3.32 (1 H, s), 3.76 (8 H, d), 4.66 (2 H, s), 5.28 (2 H,s), 6.59 (1 H, s), 6.69 (2 H, d), 6.79 (1 H, dt), 7.16-7.35 (4 H, m).LC-MS (ES, m/z): 483. 136 XIV

2-[(1-[[2-(Dimethylamino)-6-fluoro- phenyl]methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3- yl)methoxy)-2-methylpropanoic acid ¹H-NMR(400 MHz, DMSO) δ 1.44 (s, 6H), 2.48 (s, 6H), 3.83 (s, 3H), 4.49 (s,2H), 5.44 (s, 2H), 6.43 (s, 1H), 6.75 (t, 1H), 6.87-7.06 (m, 4H), 7.23(td, 1H), 7.35 (t, 1H). LC- MS (ES, m/z): 441. 137 XII

2-([5-(3-Methoxyphenyl)-1-(2- methylpropyl)-1H-pyrazol-3-yl)methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, MeOD) δ 0.76 (d,6H), 1.28-1.38 (m, 3H), 1.52 (s, 6H), 2.07 (dt, 1H), 3.85 (s, 3H), 3.96(d, 2H), 4.55 (s, 2H), 6.38 (s, 1H), 6.94-7.07 (m, 3H), 7.41 (t, 1H).LC- MS (ES, m/z): 347. 138 XII

2-([5-(3-Methoxyphenyl)-1-([oxan-4- yl]methyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, MeOD) δ 1.13 (qd,2H), 1.28-1.41 (m, 5H), 1.52 (s, 6H), 2.06 (dq, 1H), 3.23-3.34 (m, 2H),3.86 (s, 5H), 4.05 (d, 2H), 4.54 (s, 2H), 6.37 (d, 1H), 6.95-7.08 (m,3H), 7.43 (t, 1H). LC-MS (ES, m/z): 389. 139 XI

2-([1-[(3-Chloropyridin-2-yl)methyl]- 5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid ¹H-NMR (400 MHz, MeOD) δ 8.37 (dd, J= 4.7, 1.4 Hz, 1H), 7.89 (dd, J = 8.1, 1.5 Hz, 1H), 7.38-7.24 (m, 4H),6.91-6.83 (m, 1H), 6.71 (s, 1H), 5.87 (s, 2H), 4.64 (s, 2H), 3.83 (s,3H), 1.42 (s, 6H). LC-MS (ES, m/z): 416. 140 XI

2-([5-(3-Methoxyphenyl)-1-[[2- (propan-2-yloxy)phenyl]methyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid ¹H-NMR (300 MHz, MeOD) δ1.25 (6 H, d), 1.52 (6 H, s), 3.64 (3 H, s), 4.57 (2 H, s), 4.59-4.68 (1H, m), 5.30 (2 H, s), 6.51 (1 H, s), 6.67 (1 H, dd), 6.78-6.88 (2 H, m),6.90-7.00 (3 H, m), 7.19-7.26 (1 H, m), 7.29 (1 H, dd). LC-MS (ES, m/z):439. 141 XI

2-([1-[(2-Ethoxyphenyl)methyl]-5-(3- methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid. LC-MS (ES, m/z): 425 ¹H-NMR (400MHz, CDCl₃) δ 1.33 (3 H, t), 1.56 (6 H, s), 3.68 (3 H, s), 4.00 (2 H,q), 4.65 (2 H, s), 5.40 (2 H, s), 6.43 (1 H, s), 6.77-6.82 (1 H, m),6.83-6.89 (3 H, m), 6.89-6.98 (2 H, m), 7.16-7. 24 (1 H, m), 7.26- 7.32(1 H, m). 142 XI

2-([1-[(2- Cyclopropoxyphenyl)methyl]-5-(3- methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 437 ¹H-NMR (300 MHz,MeOD) δ 7.27 (m, 3H), 6.94 (m, 2H), 6.88 (m, 1H), 6.82 (dd, J = 2.6, 1.5Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 6.48 (s, 1H), 5.25 (s, 2H), 4.56 (s,2H), 3.77 (tt, J = 6.0, 6.0, 3.0, 3.0 Hz, 1H), 3.67 (s, 3H), 1.51 (s,6H), 0.75 (m, 2H), 0.58 (m, 2H).

Example 143:(3E)-4-[1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoicAcid

(ii)([1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methyl)triphenylphosphoniumBromide

To a solution of Int. G-1 (2.4 g, 6.13 mmol, 1.00 equiv) in toluene (20mL) was added PPh3 (2.4 g, 9.15 mmol, 1.50 equiv) at room temperature.The resulting solution was stirred for 3 h at 110° C. The solids werecollected by filtration. The solid was dried in an oven under reducedpressure. This resulted in the title compound as a white solid (2.2 g,55%).

(iii) Methyl(3E)-4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoate

To a solution of([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]methyl)triphenylphosphoniumbromide (500 mg, 0.76 mmol, 1.00 equiv) in THF (20 mL) was added methyl2,2-dimethyl-3-oxopropanoate (200 mg, 1.54 mmol, 2.00 equiv). This wasfollowed by the addition of NaH (50 mg, 1.25 mmol, 2.00 equiv), inportions at 0° C. The resulting solution was stirred for 16 h at roomtemperature then quenched by the addition of water/ice. The resultingsolution was diluted with 100 mL of EtOAc, then washed with 2×50 mL ofbrine. The mixture was dried over Na₂SO₄ and concentrated under vacuum.The residue was applied onto a Prep-TLC with EtOAc/petroleum ether(1:2). This resulted in the title compound as a colorless oil (125 mg,38%).

(iv)(3E)-4-[1-[(2-Chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoicacid was obtained analogously as described in Step iv of Example 101using methyl(3E)-4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoateas starting material. ¹H-NMR (400 MHz, MeOD) δ 1.42 (s, 6H), 3.69 (s,3H), 5.43 (s, 2H), 6.49 (d, 1H), 6.56-6.68 (m, 2H), 6.71-6.79 (m, 1H),6.84 (dd, 1H), 6.90-7.06 (m, 2H), 7.23-7.47 (m, 5H). LC-MS (ES, m/z):411.

Example 144:4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbutanoicAcid

(i) Methyl(3E)-4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoatewas obtained as in Steps i-iii of Example 143.

(ii) Methyl 4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbutanoate

To a solution of methyl(3E)-4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbut-3-enoate(60 mg, 0.14 mmol, 1.00 equiv) in EtOAc/MeOH (10/10 mL) was added Pd/C(20 mg). The resulting solution was stirred for 3 h under H₂ at roomtemperature. The solids were removed by filtration. The resultingmixture was concentrated under vacuum. The residue was purified byPrep-TLC with 20:1 CH₂Cl₂:MeOH. This resulted in the title compound as acolorless oil (40 mg, 66%).

(iii) 4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbutanoicacid was obtained analogously as described in Step iv of Example 101using methyl4-[1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]-2,2-dimethylbutanoateas starting material. ¹H-NMR (400 MHz, MeOD) δ 1.26-1.38 (m, 6H), 1.98(s, 2H), 2.69 (s, 2H), 3.68 (s, 3H), 5.41 (s, 2H), 6.35 (s, 1H), 6.69(dd, 1H), 6.81 (dd, 1H), 6.87-7.00 (m, 2H), 7.23-7.36 (m, 3H), 7.38-7.45(m, 1H). LC-MS (ES, m/z): 413.

Examples 145-149 are intentionally left blank.

Example 150:2-([1-[(2-Chlorophenyl)methyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoicAcid

To a solution of Int. H-64 (120 mg, 0.26 mmol, 1.00 equiv) inTHF/H₂O/MeOH (8/4/4 mL) was added LiOH (37 mg, 1.54 mmol, 6.00 equiv),in portions at room temperature. The resulting solution was stirred for2 h at room temperature. The pH was then adjusted to 3-4 with aq HCl.The resulting solution was extracted with 100 mL EtOAc, and the combinedorganic layers were dried over Na₂SO₄ and concentrated under vacuum. Thecrude product (100 mg) was purified by Prep-HPLC with the followingconditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Prep OBDC18 Column, 30??150 mm 5 um; mobile phase, Water (0.1% FA) and ACN(38.0% ACN up to 65.0% in 7 min); Detector, uv 254/220 nm, to afford 42mg (36%) of the title compound as a white solid. LC-MS: (ES, m/z): 453.¹H-NMR: (DMSO) δ: 12.70 (s, 1H), 8.09 (d, J=0.9 Hz, 1H), 7.80 (dd,J=8.4, 0.8 Hz, 1H), 7.70 (t, J=1.1 Hz, 1H), 7.48-7.37 (m, 1H), 7.36-7.23(m, 2H), 7.14 (dd, J=8.4, 1.3 Hz, 1H), 6.86-6.75 (m, 1H), 6.55 (s, 1H),5.47 (s, 2H), 4.46 (s, 2H), 4.41 (q, J=0.9 Hz, 2H), 1.42 (s, 6H), 1.36(t, J=0.6 Hz, 3H).

Example 151: Sodium2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate

A solution of2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicacid (Example 150, 50 mg, 0.11 mmol, 1.00 equiv) and NaOH (18 mg, 0.45mmol, 4.00 equiv) in MeOH/H₂O (5/2 mL) was stirred for 3 h at rt, thenpurified by Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, XBridge Shield RP18 OBDColumn, 5 um, 19*150 mm; mobile phase, Water(10 MMOL/L NH4HCO3) andMeOH— (15.0% MeOH— up to 95.0% in 7 min); Detector, UV 254/220 nm, toafford 20.9 mg (40%) of the title compound as a white solid. LC-MS: (ES,m/z): 453.00. ¹H NMR (300 MHz, DMSO) δ 8.07 (s, 1H), 7.77 (d, J=8.3 Hz,1H), 7.65 (s, 1H), 7.41 (m, 1H), 7.28 (m, 2H), 7.10 (d, J=8.4 Hz, 1H),6.79 (m, 1H), 6.56 (s, 1H), 5.46 (s, 2H), 4.49 (s, 2H), 4.37 (q, J=7.2,7.2, 7.2 Hz, 2H), 1.34 (d, J=17.1 Hz, 9H).

Example 152:2-([5-(3-Cyclopropoxyphenyl)-1-(1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

(i)2-([5-(3-Cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

A solution of Int. H-76 (100 mg, 0.17 mmol, 1.00 equiv) and LiOH (20 mg,0.84 mmol, 4.00 equiv) in THF/H₂O (4/1 mL) was stirred for 2 h at roomtemperature, then cooled to 0° C. The pH was adjusted to 1 with 1 M HCl.The resulting solution was extracted with 2×100 mL EtOAc, and thecombined organic layers were washed with 100 mL of brine, dried overNa₂SO₄ and concentrated under vacuum, to afford 50 mg (51%) of the titlecompound as a white solid. LC-MS: (ES, m/z): 563.

(ii)2-([5-(3-Cyclopropoxyphenyl)-1-(1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

A solution of the product from the previous step (50 mg, 0.09 mmol, 1.00equiv) and TFA (3 mL) in CH₂Cl₂ (10 mL) was stirred for 5 h at roomtemperature, then concentrated under vacuum. The crude product (50 mg)was purified by Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, Xselect CSH OBD Column30*150 mm 5 um, n; mobile phase, Water (0.1% FA) and ACN (43.0% ACN upto 55.0% in 7 min); Detector, UV 254/220 nm, to afford 15 mg (39%) ofthe title compound as a white solid. LC-MS: (ES, m/z): 433. ¹H NMR (300MHz, DMSO-d₆) δ 13.09 (s, 1H), 8.18 (s, 1H), 7.81 (dd, J=7.0, 2.0 Hz,1H), 7.20 (t, J=7.9 Hz, 1H), 7.14-7.02 (m, 2H), 6.95-6.85 (m, 2H),6.85-6.80 (m, 1H), 6.71 (s, 1H), 4.55 (s, 2H), 3.45 (tt, J=6.3, 3.0 Hz,1H), 1.44 (s, 6H), 0.58-0.43 (m, 2H), 0.43-0.26 (m, 2H).

Example 153:2-([5-(3-Cyclopropoxyphenyl)-1-(1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

(i)2-([5-(3-cyclopropoxyphenyl)-1-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

A solution of Int. H-77 (160 mg, 0.28 mmol, 1.00 equiv) and LiOH (70 mg,2.92 mmol, 10.54 equiv) in THF/MeOH/H₂O (5/1/1 mL) was stirred for 3 hat room temperature. The pH value was adjusted to 5 with 1 M HCl. Theresulting solution was extracted with 3×20 mL EtOAc. The combinedorganic layers were concentrated under reduced pressure and dried, toafford 140 mg (90%) of the title compound as light yellow oil. LC-MS:(ES, m/z):563.2.

(ii)2-([5-(3-Cyclopropoxyphenyl)-1-(1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

A solution of the product from the previous step (140 mg, 0.25 mmol,1.00 equiv) and HCl/dioxane (5 mL) was stirred for 3 h at roomtemperature, then concentrated under vacuum. The crude product (100 mg)was purified by Prep-HPLC with the following conditions(2#-AnalyseHPLC-SHIMADZU(HPLC-10)): Column, Xselect CSH F-Phenyl OBDColumn 19*150 mm Sum, n; mobile phase, Water (0.1% FA) and ACN (35.0%ACN up to 45.0% in 7 min); Detector, uv 254/220 nm, to afford 18.9 mg(18%) of the title compound as a white solid. LC-MS: (ES, m/z):433.05.¹H NMR (300 MHz, DMSO) δ 13.29 (s, 1H), 7.69 (d, J=1.0 Hz, 1H), 7.57 (d,J=8.4 Hz, 1H), 7.35 (dd, J=8.4, 7.3 Hz, 1H), 7.21 (t, J=7.9, 7.9 Hz,1H), 6.91 (dtd, J=8.3, 5.8, 4.8, 3.0 Hz, 3H), 6.81 (m, 1H), 6.70 (s,1H), 4.53 (s, 2H), 3.52 (tt, J=6.2, 6.2, 3.0, 3.0 Hz, 1H), 1.44 (s, 6H),0.46 (m, 2H), 0.36 (m, 2H).

Example 154:2-([5-(3-cyclopropoxyphenyl)-1-(3-methyl-1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

(i)2-([5-(3-cyclopropoxyphenyl)-1-(3-methyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

A solution of Int. H-78 (100 mg, 0.17 mmol, 1.00 equiv) and LiOH (40 mg,1.67 mmol, 10.00 equiv) in THF/MeOH/H₂O (5/1/1 mL) was stirred for 3 hat room temperature. The pH value of the solution was adjusted to 5 with1 M HCl. The resulting solution was extracted with 3×15 mL of EtOAc. Thecombined organic layers were dried over Na₂SO₄ and concentrated undervacuum, to afford 80 mg (82%) of the title compound as light yellow oil.LC-MS: (ES, m/z):577.3.

(ii)2-([5-(3-cyclopropoxyphenyl)-1-(3-methyl-1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoicAcid

A solution of the product from the previous step (80 mg, 0.14 mmol, 1.00equiv) in HCl/dioxane (5 mL) was stirred 3 h at room temperature, thenconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (2#-AnalyseHPLC-SHIMADZU(HPLC-10)):Column, Xselect CSH OBD Column 30*150 mm Sum, n; mobile phase, Water(0.1% FA) and ACN (40.0% ACN up to 50.0% in 7 min); Detector, UV 254/220nm, to afford 8.2 mg (13%) of the title compound as a white solid.LC-MS: (ES, m/z): 447.15. ¹H NMR (300 MHz, MeOD) δ 7.62 (dd, J=8.5, 0.8Hz, 1H), 7.42 (dd, J=8.5, 7.2 Hz, 1H), 7.17 (t, J=7.9, 7.9 Hz, 1H), 6.99(m, 2H), 6.80 (m, 3H), 4.65 (s, 2H), 3.25 (dt, J=5.7, 2.6, 2.6 Hz, 1H),2.07 (s, 3H), 1.54 (s, 6H), 0.41 (m, 4H).

The following substituted pyrazole carboxylic acids were obtained fromLiOH hydrolysis of the corresponding methyl esters:

TABLE 25 Examples 155-276. IUPAC Name Purification Ex. Ester StructureAnalytical data 155 H-134

2-([1-[2-(Azetidin-1-yl)phenyl]-5-[3- (2,2-dimethylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XSelect: 63% ACN up to 83%in 7 min LC-MS: (ES, m/z): 478.25. ¹H NMR (300 MHz, MeOD) δ 7.30 (ddd, J= 8.6, 7.4, 1.6 Hz, 1H), 7.20 (t, J = 7.9, 7.9 Hz, 1H), 7.03 (m, 2H),6.87 (t, J = 2.0, 2.0 Hz, 1H), 6.82 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H),6.75 (td, J = 7.6, 7.5, 1.3 Hz, 1H), 6.70 (s, 1H), 6.55 (dd, J = 8.2,1.3 Hz, 1H), 4.59 (s, 2H), 3.57 (d, J = 21.2 Hz, 4H), 2.13 (p, J = 7.3,7.3, 7.3, 7.3 Hz, 2H), 1.53 (s, 6H), 0.98 (s, 9H). 156 H-38

2-([1-(2-Chlorophenyl)-5-(pyridin-2-yl)- 1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 10% ACN up to 67% in 7 min LC-MS: (ES,m/z): 371.95. H-NMR: ¹H NMR (300 MHz, DMSO) δ 12.68 (s, 1H), 8.31 (ddd,J = 4.9, 1.8, 0.9 Hz, 1H), 7.77 (td, J = 7.8, 7.7, 1.8 Hz, 1H), 7.51 (m,5H), 7.24 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 6.96 (s, 1H), 4.49 (s, 2H),1.43 (s, 6H). 157 H-40

2-([1-(2-chlorophenyl)-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoic acid XBridge:30% ACN up to 57% in 7 min LC-MS: (ES, m/z): 381. ¹H-NMR: (DMSO, ppm) δ:8.02 (d, J = 1.1 Hz, 1H), 7.89-7.75 (m, 1H), 7.73- 7.47 (m, 5H), 7.34(d, J = 1.4 Hz, 1H), 6.95 (dt, J = 8.4, 1.4 Hz, 1H), 4.44-4.22 (m, 2H),3.88 (d, J = 1.4 Hz, 3H), 1.24 (td, J = 7.1, 1.4 Hz, 3H). 158 H-27

2-([1-(2-Fluorophcnyl)-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXBridge: 25% ACN up to 60% in 7 min LC-MSO: (ES, m/z): 441. ¹H NMR:(DMSO) δ: 12.71 (s, 1H), 7.63-7.47 (m, 2H), 7.40-7.29 (m, 2H), 7.22 (t,J = 8.0 Hz, 1H), 6.91 (ddd, J = 8.4, 2.6, 1.0 Hz, 1H), 6.85-6.68 (m,3H), 4.67 (dd, J = 7.9, 6.0 Hz, 2H), 4.49 (s, 2H), 4.35 (t, J = 6.0 Hz,2H), 4.09 (d, J = 6.8 Hz, 2H), 3.34-3.23 (m, 1H), 1.43 (s, 6H). 159 H-28

2-([5-(3-Cyclobutoxyphenyl)-1-(2- fluorophenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 47% ACN up to 67% in 7 minLC-MS: (ES, m/z): 425. ¹H NMR: (400 MHz, DMSO-d6) δ 7.65- 7.48 (m, 2H),7.41-7.29 (m, 2H), 7.23 (t, J = 8.0 Hz, 1H), 6.93-6.74 (m, 2H), 6.67 (s,1H), 6.57 (dd, J = 2.5, 1.5 Hz, 1H), 4.48 (s, 2H), 4.43 (q, J = 7.1 Hz,1H), 2.23 (dddd, J = 9.2, 7.8, 6.5, 2.6 Hz, 2H), 1.91 (qdd, J = 9.8,7.7, 2.7 Hz, 2H), 1.78-1.66 (m, 1H), 1.64-1.50 (m, 1H), 1.43 (s, 6H).160 H-29

2-([1-(2-Fluorophenyl)-5-[3-(oxetan-3- yloxy)phenyl]-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 28% ACN up to 54% in 7 minLC-MS: (ES, m/z): 427. ¹H NMR: (300 MHz, DMSO) δ 7.58 (td, J = 8.0, 7.8,1.9 Hz, 1H), 7.51 (m, 1H), 7.36 (m, 2H), 7.27 (m, 1H), 6.88 (dt, J =7.7, 1.2, 1.2 Hz, 1H), 6.77 (ddd, J = 8.3, 2.6, 0.9 Hz, 1H), 6.68 (s,1H), 6.49 (dd, J = 2.6, 1.5 Hz, 1H), 5.09 (m, 1H), 4.73 (m, 2H), 4.48(s, 2H), 4.37 (m, 2H), 1.42 (s, 6H). 161 H-5

2-([5-(3-Cyclobutoxyphenyl)-1-(2- methylphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 48% ACN up to 69% in 7 minLC-MS: (ES, m/z): 421. ¹H NMR: (400 MHz, DMSO-d₆) δ 12.70 (s, 1H),7.45-7.25 (m, 4H), 7.20 (t, J = 8.0 Hz, 1H), 6.90-6.81 (m, 1H), 6.75(dd, J = 8.2, 2.4 Hz, 1H), 6.66 (s, 1H), 6.55-6.45 (m, 1H), 4.48 (s,2H), 4.34 (p, J = 7.2 Hz, 1H), 2.22 (dddt, J = 11.6, 8.7, 5.9, 2.4 Hz,2H), 1.92 (ddd, J = 9.8, 7.6, 2.7 Hz, 2H), 1.88 (s, 3H), 1.71 (dd, J =11.7, 8.5 Hz, 1H), 1.57 (tt, J = 10.1, 8.1 Hz, 1H), 1.43 (s, 6H). 162H-30

2-([5-(3,5-Diethoxyphenyl)-1-(2-methyl-phenyl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XSelect: 48%ACN up to 75% in 7 min LC-MS: (ES, m/z): 439.15. ¹H NMR (300 MHz, DMSO)δ 12.70 (s, 1H), 7.32 (m, 4H), 6.68 (s, 1H), 6.35 (t, J = 2.2, 2.2 Hz,1H), 6.28 (d, J = 2.2 Hz, 2H), 4.48 (s, 2H), 3.81 (q, J = 6.9, 6.9, 6.9Hz, 4H), 1.87 (s, 3H), 1.42 (s, 6H), 1.19 (t, J = 6.9, 6.9 Hz, 6H). 163H-82

2-([1-[2-(dimethylamino)phenyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXSelect: 35% ACN up to 65% in 7 min LC-MS (ES, m/z): 448.20. ¹H NMR (300MHz, DMSO) δ 8.16 (s, 0.12H), 7.97 (d, J = 0.9 Hz, 1H), 7.60 (dd, J =8.4, 0.8 Hz, 1H), 7.32 (m, 3H), 6.98 (m, 2H), 6.85 (dd, J = 8.2, 1.3 Hz,1H), 6.73 (s, 1H), 4.52 (s, 2H), 4.25 (q, J = 7.1, 7.1, 7.1 Hz, 2H),2.13 (s, 6H), 1.43 (s, 6H), 1.20 (t, J = 7.2, 7.2 Hz, 3H). 164 H-31

2-([5-(3,5-Dimethoxyphenyl)-1-(2- ethoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 35% ACN up to 65% in 7 minLC-MS: (ES, m/z): 441. ¹H NMR: (300 MHz, MeOH-d₄) δ 7.44 (td, J = 7.6,1.5 Hz, 2H), 7.15-6.99 (m, 2H), 6.68 (s, 1H), 6.44-6.35 (m, 3H), 4.61(s, 2H), 3.82 (d, J = 18.7 Hz, 2H), 3.62 (s, 6H), 1.55 (s, 6H), 1.06 (t,J = 7.0 Hz, 3H). 165 H-6

2-([5-(1-Ethyl-1H-indazol-6-yl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXSelect: 30% ACN up to 53% in 7 min LC-MS: (ES, m/z): 459. ¹H NMR (300MHz, DMSO-d₆) δ 12.75 (s, 1H), 8.16 (s, 1H), 7.96 (d, J = 0.9 Hz, 1H),7.89 (dd, J = 8.2, 1.0 Hz, 1H), 7.63- 7.51 (m, 2H), 7.45 (dd, J = 7.3,1.0 Hz, 1H), 7.17 (dd, J = 8.1, 7.3 Hz, 1H), 6.94 (dd, J = 8.4, 1.4 Hz,1H), 6.89 (s, 1H), 4.56 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.47 (s, 3H),1.45 (s, 6H), 1.16 (t, J = 7.1 Hz, 3H). 166 H-7

2-([5-(3-Cyclobutoxyphenyl)-1-(1- methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 53% ACN up to 78% in 7 minLC-MS: (ES, m/z): 461. ¹H NMR: (300 MHz, DMSO-d₆) δ 12.71 (s, 1H), 8.22(s, 1H), 7.94 (dd, J = 8.1, 1.0 Hz, 1H), 7.39 (dd, J = 7.3, 1.0 Hz, 1H),7.27- 7.13 (m, 2H), 6.90 (dt, J = 7.8, 1.2 Hz, 1H), 6.80 (s, 1H), 6.72(ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.50-6.42 (m, 1H), 4.54 (s, 2H), 4.14(p, J = 7.0 Hz, 1H), 3.45 (s, 3H), 2.01 (d, J = 9.2 Hz, 2H), 1.89- 1.74(m, 2H), 1.74-1.59 (m, 1H), 1.57- 1.47 (m, 1H), 1.44 (s, 6H). 167 H-8

2-([5-[3-(2,2-dimethylpropoxy)phenyl]- 1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methyl- propanoic acid XSelect: 50% ACN up to80% in 7 min LC-MS: (ES, m/z): 477.20. ¹H NMR: (300 MHz, DMSO) δ 8.18(s, 1H), 7.91 (dd, J = 8.1, 1.0 Hz, 1H), 7.39 (dd, J = 7.3, 1.0 Hz, 1H),7.16 (m, 2H), 6.80 (m, 3H), 6.63 (dd, J = 2.5, 1.5 Hz, 1H), 4.54 (s,2H), 3.43 (s, 3H), 3.17 (s, 2H), 1.44 (s, 6H), 0.87 (s, 9H). 168 H-9

2-([5-[3-(cyclobutylmethoxy)phenyl]-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol- 3-yl]methoxy)-2-methylpropanoicacid XSelect: 45% ACN up to 80% in 8 min LC-MS: (ES, m/z): 475. ¹H NMR:(300 MHz, DMSO-d₆) δ 12.73 (s, 1H), 8.20 (s, 1H), 7.93 (dd, J = 8.1, 1.0Hz, 1H), 7.40 (dd, J = 7.3, 1.0 Hz, 1H), 7.30-7.10 (m, 2H), 6.94-6.76(m, 3H), 6.67 (dd, J = 2.5, 1.6 Hz, 1H), 4.54 (s, 2H), 3.57 (d, J = 6.8Hz, 2H), 3.44 (s, 3H), 2.46 (d, J = 7.4 Hz, 1H), 2.05-1.76 (m, 4H),1.74-1.55 (m, 2H), 1.44 (s, 6H). 169 H-32

2-([5-[3-(Cyclopropylmethoxy)phenyl]- 1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XSelect: 40% ACN up to 70%in 7 min LC-MS: (ES, m/z): 461. ¹H NMR: (300 MHz, DMSO-d₆) δ 12.71 (s,1H), 8.19 (s, 1H), 7.91 (dd, J = 8.1, 1.0 Hz, 1H), 7.40 (dd, J = 7.3,1.0 Hz, 1H), 7.28-7.04 (m, 2H), 6.80 (d, J = 8.0 Hz, 3H), 6.72-6.58 (m,1H), 4.54 (s, 2H), 3.48 (d, J = 7.0 Hz, 2H), 3.44 (s, 3H), 1.44 (s, 6H),1.00 (dddd, J = 15.0, 10.1, 5.1, 2.3 Hz, 1H), 0.55-0.43 (m, 2H),0.25-0.11 (m, 2H). 170 H-10

2-methyl-2-([1-(1-methyl-1H-indazol-7-yl)-5-[3-(2-methylpropoxy)phenyl]-1H- pyrazol-3-yl]methoxy]propanoicacid XSelect: 50% ACN up to 80% in 7 min LC-MS: (ES, m/z): 463. ¹H NMR:(300 MHz, DMSO-d₆) δ 12.73 (s, 1H), 8.18 (s, 1H), 7.91 (dd, J = 8.1, 1.0Hz, 1H), 7.39 (dd, J = 7.3, 1.0 Hz, 1H), 7.26-7.05 (m, 2H), 6.94-6.73(m, 3H), 6.63 (dd, J = 2.5, 1.6 Hz, 1H), 4.53 (s, 2H), 3.43 (s, 3H),3.34 (d, J = 6.7 Hz, 2H), 1.79 (hept, J = 6.7 Hz, 1H), 1.43 (s, 6H),0.84 (d, J = 6.7 Hz, 6H). 171 H-34

2-([5-(3,5-Diethoxyphenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXSelect: 45% ACN up to 81% in 7 min LC-MS: (ES, m/z): 479.15. ¹H NMR:(300 MHz, DMSO) δ 12.70 (m, 1H), 8.18 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H),7.44 (d, J = 7.2 Hz, 1H), 7.20 (t, J = 7.7, 7.7 Hz, 1H), 6.81 (s, 1H),6.31 (s, 3H), 4.53 (s, 2H), 3.73 (q, J = 7.0, 6.9, 6.9 Hz, 4H), 3.41 (s,3H), 1.44 (s, 6H), 1.13 (t, J = 6.9, 6.9 Hz, 6H). 172 H-11

2-([5-[3-(2,2-Dimethylpropoxy)phenyl]-1-(1-ethyl-1H-indazol-7-yl)-1H-pyrazol- 3-yl]methoxy)-2-methylpropanoicacid XSelect: 50% ACN up to 85% in 7 min LC-MS: (ES, m/z): 491. ¹H NMR:(300 MHz, DMSO-d₆) δ 12.67 (s, 1H), 8.24 (s, 1H), 7.92 (dd, J = 8.1, 1.1Hz, 1H), 7.32 (dd, J = 7.3, 1.1 Hz, 1H), 7.24-6.98 (m, 2H), 6.85 (s,1H), 6.79 (dddd, J = 7.2, 6.4, 2.5, 1.0 Hz, 2H), 6.65-6.55 (m, 1H), 4.53(s, 2H), 3.71 (d, J = 36.9 Hz, 2H), 3.15 (s, 2H), 1.43 (s, 6H), 1.09 (t,J = 7.1 Hz, 3H), 0.86 (s, 9H). 173 H-37

2-([1-(2-Chlorophenyl)-5-[3-(oxetan-3-ylmethoxy)phenyl]-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXBridge: 25% ACN up to 60% in 7 min LC-MS: (ES, m/z): 457.0. ¹H-NMR: δ_(H) (300 MHz, DMSO-d₆) 12.70 (s, 1H), 7.64-7.45 (m, 4H), 7.20 (t, J =8.0 Hz, 1H), 6.88 (ddd, J = 8.4, 2.5, 1.0 Hz, 1H), 6.82-6.69 (m, 3H),4.67 (dd, J = 7.9, 6.0 Hz, 2H), 4.49 (s, 2H), 4.35 (t, J = 6.0 Hz, 2H),4.06 (d, J = 6.8 Hz, 2H), 3.34-3.22 (m, 1H), 1.43 (s, 6H). 174 H-39

2-([1-(2-Chlorophenyl)-5-(1-methyl-1H-indazol-6-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylpropanoic acid XBridge:25% ACN up to 58% in 7 min LC-MS: (ES, m/z): 425. ¹H NMR: (400 MHz,DMSO-d₆) δ 12.75 (s, 1H), 8.01 (d, J = 1.0 Hz, 1H), 7.66- 7.60 (m, 2H),7.58 (ddd, J = 4.0, 3.0, 1.9 Hz, 2H), 7.54-7.46 (m, 2H), 6.85 (dd, J =8.4, 1.4 Hz, 1H), 6.79 (s, 1H), 4.52 (s, 2H), 3.95 (s, 3H), 1.45 (s,6H). 175 H-41

2-([1-(2-Chlorophenyl)-5-(3-cyclo- butoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 47% ACN up to 67% in 7 minLC-MS: (ES, m/z): 441. ¹H-NMR: ¹H NMR (400 MHz, DMSO- d₆) δ 12.71 (s,1H), 7.60 (ddd, J = 12.7, 7.5, 2.0 Hz, 2H), 7.56-7.46 (m, 2H), 7.21 (t,J = 8.0 Hz, 1H), 6.84 (dt, J = 7.7, 1.2 Hz, 1H), 6.77 (ddd, J = 8.3,2.5, 1.0 Hz, 1H), 6.68 (s, 1H), 6.53 (t, J = 2.0 Hz, 1H), 4.48 (s, 2H),4.38 (p, J = 7.2 Hz, 1H), 2.31-2.18 (m, 2H), 1.91 (qdd, J = 9.6, 7.5,2.8 Hz, 2H), 1.73 (qt, J = 10.1, 2.7 Hz, 1H), 1.65-1.50 (m, 1H), 1.43(s, 6H). 176 H-42

2-([1-(2-Chlorophenyl)-5-[3-(oxetan-3- yloxy)phenyl]-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 25% ACN up to 60% in 7 minLC-MS: (ES, m/z): 443. ¹H NMR: (300 MHz, DMSO) δ 12.72 (s, 1H), 7.60(ddd, J = 6.2, 4.2, 2.7 Hz, 2H), 7.51 (ddd, J = 6.3, 3.5, 2.2 Hz, 2H),7.24 (t, J = 8.0, 8.0 Hz, 1H), 6.87 (dt, J = 7.8, 1.1, 1.1 Hz, 1H), 6.74(ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 6.68 (s, 1H), 6.45 (dd, J = 2.6, 1.5Hz, 1H), 5.06 (ddd, J = 6.0, 4.9, 1.1 Hz, 1H), 4.77 (m, 2H), 4.48 (s,2H), 4.39 (m, 2H), 1.42 (s, 6H). 177 H-43

2-([1-(2-chlorophenyl)-5-[3-(2,2- dimethylpropoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 0.1% DEA/57.0% ACN up to 85%ACN in 7 min LC-MS: (ES, m/z): 457.05. ¹H NMR (300 MHz, DMSO) δ 12.70(s, 1H), 7.58 (m, 2H), 7.50 (m, 2H), 7.17 (t, J = 8.0, 8.0 Hz, 1H), 6.83(ddd, J = 8.4, 2.5, 1.0 Hz, 1H), 6.75 (dt, J = 7.7, 1.2, 1.2 Hz, 1H),6.70 (d, J = 3.1 Hz, 2H), 4.48 (s, 2H), 3.40 (s, 2H), 1.42 (s, 6H), 0.92(s, 9H). 178 H-44

2-([1-(2-Chlorophenyl)-5-[3- (Cyclobutylmethoxy)phenyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XSelect: 55% up to 85% in7 min LC-MS: (ES, m/z): 455.09. ¹H NMR: (300 MHz, DMSO) δ 12.72 (s, 1H),7.58 (ddd, J = 6.5, 4.9, 2.5 Hz, 2H), 7.49 (m, 2H), 7.17 (t, J = 8.0,8.0 Hz, 1H), 6.82 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 6.77 (m, 1H), 6.70(d, J = 2.9 Hz, 2H), 4.49 (s, 2H), 3.74 (d, J = 6.8 Hz, 2H), 2.55 (m,1H), 1.99 (m, 2H), 1.85 (m, 2H), 1.73 (m, 2H), 1.43 (s, 6H). 179 H-45

2-([1-(2-Chlorophenyl)-5-(3,5- dimethoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 38% ACN up to 57% in 7 minLC-MS: (ES, m/z): 431. ¹H NMR: (300 MHz, MeOH-d₄) δ 7.61- 7.42 (m, 4H),6.73 (s, 1H), 6.38 (dd, J = 9.8, 2.2 Hz, 3H), 4.61 (s, 2H), 3.63 (s,6H), 1.53 (s, 6H). 180 H-12

2-([1-(2-Chlorophenyl)-5-(3,5-diethoxy-phenyl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XBridge: 42%ACN up to 68% in 7 min LC-MS: (ES, m/z): 459.05. ¹H NMR: (300 MHz, DMSO)δ 12.74 (s, 1H), δ 7.51 (m, 4H), 6.70 (s, 1H), 6.38 (t, J = 2.3, 2.3 Hz,1H), 6.30 (d, J = 2.2 Hz, 2H), 4.48 (s, 2H), 3.84 (q, J = 7.0, 7.0, 7.0Hz, 4H), 1.42 (s, 6H), 1.22 (t, J = 7.0, 7.0 Hz, 6H). 181 H-13

2-([5-(3-cyclopropoxyphenyl)-1-(2- fluorophenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoate SunFire: 69% ACN up to 71% in 8 minLC-MS: (ES, m/z): 411.3. ¹H-NMR: δ _(H) (400 MHz, DMSO-d₆) 12.73 (1 H,s), 7.54 (2 H, m), 7.35 (2 H, m), 7.26 (1 H, t, J = 7.9, 7.9 Hz), 6.95(1 H, ddd, J = 8.3, 2.5, 1.0 Hz), 6.88 (2 H, m), 6.68 (1 H, s), 4.48 (2H, s), 3.62 (1 H, tt, J = 6.0, 6.0, 3.0, 3.0 Hz), 1.43 (6 H, s), 0.62 (2H, m), 0.50 (2 H, m). 182 H-46

2-([1-(2-Bromophenyl)-5-(3-cyclo- propoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 38% ACN up to 70% in 7 minLC-MS: (ES, m/z): 471. ¹H NMR: (DMSO) δ: 12.71 (s, 1H), 7.81- 7.71 (m,1H), 7.59-7.37 (m, 3H), 7.23 (t, J = 8.0 Hz, 1H), 6.96-6.78 (m, 3H),6.67 (s, 1H), 4.47 (s, 2H), 3.55 (tt, J = 6.0, 2.9 Hz, 1H), 1.42 (s,6H), 0.71- 0.43 (m, 4H). 183 H-149

2-([1-[2-(Azetidin-1-yl)-4-fluorophenyl]-5-(3-cyclopropoxyphenyl)-1H-pyrazol- 3-yl]methoxy)-2-methylpropanoicacid XBridge: 10% ACN up to 52% in 7 min LC-MS: (ES, m/z): 466.20. ¹HNMR (300 MHz, DMSO) δ 7.26 (t, J = 8.2, 8.2 Hz, 1H), 7.00 (m, 3H), 6.92(ddd, J = 8.2, 2.4, 1.1 Hz, 1H), 6.63 (s, 1H), 6.45 (td, J = 8.4, 8.4,2.8 Hz, 1H), 6.29 (dd, J = 11.3, 2.8 Hz, 1H), 4.46 (s, 2H), 3.62 (tt, J= 6.1, 6.1, 3.0, 3.0 Hz, 1H), 3.49 (m, 4H), 2.07 (p, J = 7.2, 7.2, 7.2,7.2 Hz, 2H), 1.39 (s, 6H), 0.69 (m, 2H), 0.56 (m, 2H). 184 H-48

2-([5-(3-Cyclopropoxyphenyl)-1-(2,4- dichlorophenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 45% ACN up to 77% in 7 minLC-MS: (ES, m/z), 461.00. ¹H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 7.81(d, J = 2.2 Hz, 1H), 7.60 (m, 2H), 7.25 (t, J = 7.9, 7.9 Hz, 1H), 6.89(m, 3H), 6.68 (s, 1H), 4.48 (s, 2H), 3.63 (tt, J = 6.1, 6.1, 3.0, 3.0Hz, 1H), 1.42 (s, 6H), 0.66 (m, 2H), 0.51 (m, 2H). 185 H-49

2-([5-(3-Cyclopropoxyphenyl)-1-(2,5- dichlorophenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XSelect: 48% ACN up to 74% in 7 minLC-MS: (ES, m/z): 461.05. ¹H NMR (300 MHz, DMSO) δ 12.72 (s, 1H), 7.83(m, 1H), 7.60 (d, J = 1.5 Hz, 2H), 7.25 (t, J = 7.9, 7.9 Hz, 1H), 6.91(m, 3H), 6.69 (s, 1H), 4.50 (s, 2H), 3.61 (dt, J = 6.0, 3.1, 3.1 Hz,1H), 1.43 (s, 6H), 0.65 (dd, J = 6.2, 2.0 Hz, 2H), 0.50 (tt, J = 6.2,6.2, 3.4, 3.4 Hz, 2H). 186 H-50

2-([5-(3-Cyclopropoxyphenyl)-1-[2-(difluoromethoxy)phenyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid XBridge: 40% ACN up to 65% in 7 min LC-MS: (ES, m/z): 459. ¹H NMR:(300 MHz, DMSO-d₆) δ 12.72 (s, 1H), 7.59-7.47 (m, 2H), 7.42-7.13 (m,3H), 6.95-6.79 (m, 3H), 6.66 (d, J = 10.0 Hz, 1H), 4.47 (s, 2H), 3.57(tt, J = 6.1, 2.9 Hz, 1H), 1.42 (s, 6H), 0.67- 0.42 (m, 4H). 187 H-51

2-([5-(3-cyclopropoxyphenyl)-1-(2- ethoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 40% ACN up to 67% in 7 minLC-MS: (ES, m/z): 437. ¹H NMR: (300 MHz, MeOH-d₄) δ 7.50- 7.37 (m, 2H),7.26-7.15 (m, 1H), 7.13- 6.99 (m, 2H), 6.97-6.87 (m, 3H), 6.67 (s, 1H),4.62 (s, 2H), 3.75 (s, 2H), 3.51 (tt, J = 6.1, 3.0 Hz, 1H), 1.55 (s,6H), 1.02 (t, J = 7.0 Hz, 3H), 0.64 (d, J = 6.0 Hz, 2H), 0.57-0.47 (m,2H). 188 H-52

2-([5-(3-Cyclopropoxyphenyl)-1-(2- methylphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 40% ACN up to 67% in 7 minLC-MS: (ES, m/z): 407. ¹H NMR: (300 MHz, MeOH-d₄) δ 7.44- 7.27 (m, 4H),7.20 (t, J = 8.0 Hz, 1H), 6.92 (tt, J = 8.5, 1.1 Hz, 2H), 6.84 (t, J =2.1 Hz, 1H), 6.73 (s, 1H), 4.61 (s, 2H), 3.46 (tt, J = 6.1, 3.0 Hz, 1H),1.96 (s, 3H), 1.54 (s, 6H), 0.63 (pd, J = 6.0, 3.8 Hz, 2H), 0.57-0.48(m, 2H). 189 H-53

2-([5-(3-cyclopropoxyphenyl)-1-[2-(propan-2-yl)phenyl]-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXSelect: 50% ACN up to 76% in 7 min LC-MS: (ES, m/z): 435. ¹H-NMR:(DMSO, ppm): δ: 12.65 (s, 1H), 7.46 (dd, J = 3.7, 1.3 Hz, 2H), 7.36-7.16 (m, 3H), 6.94-6.76 (m, 3H), 6.68 (s, 1H), 4.49 (s, 2H), 3.53 (tt, J= 6.1, 2.9 Hz, 1H), 1.43 (s, 6H), 1.00 (s, 3H), 0.84 (s, 3H), 0.67-0.51(m, 2H), 0.47 (tq, J = 5.5, 3.2 Hz, 2H). 190 H-54

2-([5-(3-Cyclopropoxyphenyl)-1-[2-(trifluoromethyl)phenyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid XBridge: 40% ACN up to 63% in 7 min LC-MS: (ES, m/z): 461. ¹H NMR(300 MHz, MeOH-d₄) δ 7.94- 7.83 (m, 1H), 7.79-7.64 (m, 2H), 7.48- 7.37(m, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.91 (dddd, J = 6.4, 4.0, 2.7, 1.2Hz, 2H), 6.83 (t, J = 2.0 Hz, 1H), 6.73 (s, 1H), 4.61 (s, 2H), 3.49 (tt,J = 6.1, 3.0 Hz, 1H), 1.53 (s, 6H), 0.71-0.58 (m, 2H), 0.53 (ddd, J =6.2, 4.3, 2.8 Hz, 2H). 191 H-55

2-([5-(3-Cyclopropoxyphenyl)-1-(1- methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XBridge: 38% ACN up to 62% in 7 minLC-MS: (ES, m/z): 447. ¹H-NMR: (DMSO, ppm): δ: 12.74 (s, 1H), 8.20 (s,1H), 7.92 (dd, J = 8.1, 1.0 Hz, 1H), 7.38 (dd, J = 7.3, 1.0 Hz, 1H),7.27-7.13 (m, 2H), 6.99-6.76 (m, 4H), 4.54 (s, 2H), 3.49 (s, 3H), 3.43-3.34 (m, 1H), 1.44 (s, 6H), 0.52-0.36 (m, 4H). 192 H-14

2-([5-(3-Cyclopropoxyphenyl)-1-(1- methyl-1H-indazol-4-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 35% ACN up to 68% in 7 minLC-MS: (ES, m/z): 446. ¹H NMR: (300 MHz, DMSO-d₆) δ 7.80- 7.59 (m, 2H),7.41 (dd, J = 8.6, 7.3 Hz, 1H), 7.21 (t, J = 7.9 Hz, 1H), 7.07-6.80 (m,4H), 6.71 (s, 1H), 4.54 (s, 2H), 4.07 (s, 3H), 3.56 (tt, J = 6.1, 2.9Hz, 1H), 1.45 (s, 6H), 0.54-0.45 (m, 2H), 0.43- 0.33 (m, 2H). 193 H-15

2-([5-(3-Cyclopropoxyphenyl)-1-(1- ethyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 61% ACN up to 66% in 7 minLC-MS: (ES, m/z): 461. ¹H NMR (300 MHz, DMSO-d₆) δ 12.71 (s, 1H), 8.25(s, 1H), 7.92 (dd, J = 8.1, 1.1 Hz, 1H), 7.31 (dd, J = 7.3, 1.1 Hz, 1H),7.25-7.09 (m, 2H), 6.94 (dt, J = 7.7, 1.2 Hz, 1H), 6.91-6.81 (m, 2H),6.78 (dd, J = 2.5, 1.6 Hz, 1H), 4.55 (s, 2H), 3.77 (d, J = 28.7 Hz, 2H),3.41- 3.25 (m, J = 3.3 Hz, 1H), 1.44 (s, 6H), 1.12 (t, J = 7.1 Hz, 3H),0.57-0.29 (m, 4H). 194 H-56

2-([5-(3-Cyclopropoxyphenyl)-1-(1- methyl-1H-1,3-benzodiazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XSelect: 36% ACN up to 55%in 7 min LC-MS: (ES, m/z): 447.10. ¹H NMR (300 MHz, DMSO) δ 12.72 (s,1H), 8.18 (s, 1H), 7.78 (dd, J = 7.6, 1.5 Hz, 1H), 7.22 (m, 3H), 6.89(m, 2H), 6.79 (t, J = 2.1, 2.1 Hz, 1H), 6.77 (s, 1H), 4.52 (s, 2H), 3.41(dq, J = 6.1, 3.1, 3.0, 3.0 Hz, 1H), 3.29 (s, 3H), 1.43 (s, 6H), 0.47(d, J = 6.1 Hz, 2H), 0.39 (m, 2H). 195 H-16

2-([5-(1-Benzothiophen-2-yl)-1-[(2- chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 50% ACN up to 80% in 7 minLC-MS: (ES, m/z): 441. ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (s, 1H),8.02-7.95 (m, 1H), 7.90-7.81 (m, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.52-7.45 (m, 1H), 7.44-7.36 (m, 2H), 7.31 (pd, J = 7.4, 1.8 Hz, 2H),6.77-6.70 (m, 1H), 6.68 (s, 1H), 5.62 (s, 2H), 4.45 (s, 2H), 1.42 (s,6H). 196 H-57

2-([5-(3-Chloro-5-methoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid XSelect: 50% ACN up to 76% in 7 min LC-MS: (ES, m/z): 459.¹H-NMR-PH- VET-168-0: (DMSO): δ: 12.62 (s, 1H), 7.24 (ddd, J = 8.5, 7.4,1.8 Hz, 1H), 7.11- 6.81 (m, 5H), 6.76 (dd, J = 7.6, 1.7 Hz, 1H), 6.48(s, 1H), 5.27 (s, 2H), 4.41 (s, 2H), 3.99 (q, J = 6.9 Hz, 2H), 3.32 (s,1H), 1.40 (s, 6H), 1.22 (t, J = 6.9 Hz, 3H). 197 H-17

2-([l-[(2-Chlorophenyl)methyl]-5-(1-methyl-1H-indazol-4-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXSelect: 45% ACN up to 71% in 7 min LC-MS: (ES, m/z): 438. ¹H NMR: (300MHz, DMSO-d₆) δ 12.66 (s, 1H), 7.93 (d, J = 1.0 Hz, 1H), 7.70 (dt, J =8.5, 0.9 Hz, 1H), 7.44 (dd, J = 8.5, 7.1 Hz, 1H), 7.39-7.30 (m, 1H),7.30-7.20 (m, 2H), 7.09 (dd, J = 7.1, 0.8 Hz, 1H), 6.88-6.69 (m, 1H),6.57 (s, 1H), 5.38 (s, 2H), 4.47 (s, 2H), 4.07 (s, 3H), 1.41 (s, 6H).198 H-18

2-([1-[(2-Ethoxyphenyl)methyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXSelect: 45% ACN up to 65% in 7 min LC-MS: (ES, m/z): 463. ¹H NMR: (300MHz, DMSO-d₆) δ 12.70 (s, 1H), 8.09 (d, J = 0.9 Hz, 1H), 7.79 (dd, J =8.3, 0.8 Hz, 1H), 7.68 (q, J = 1.1 Hz, 1H), 7.30-7.11 (m, 2H), 6.95 (dd,J = 8.3, 1.1 Hz, 1H), 6.86 (td, J = 7.5, 1.1 Hz, 1H), 6.72 (dd, J = 7.6,1.7 Hz, 1H), 6.51 (s, 1H), 5.33 (s, 2H), 4.53-4.32 (m, 4H), 3.93 (q, J =6.9 Hz, 2H), 1.42 (s, 6H), 1.33 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 6.9Hz, 3H). 199 H-19

2-([5-(3-Ethoxyphenyl)-1-[(2-ethoxy- phenyl)methyl]-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XSelect: 45% ACN up to 80% in 7 minLC-MS: (ES, m/z): 439. ¹H NMR: (300 MHz, DMSO-d₆) δ 12.68 (s, 1H), 7.33(t, J = 7.9 Hz, 1H), 7.23 (ddd, J = 8.5, 7.5, 1.7 Hz, 1H), 7.03- 6.91(m, 3H), 6.91-6.82 (m, 2H), 6.69 (dd, J = 7.6, 1.7 Hz, 1H), 6.42 (s,1H), 5.26 (s, 2H), 4.42 (s, 2H), 3.96 (dq, J = 20.8, 6.9 Hz, 4H), 1.40(s, 6H), 1.25 (dt, J = 12.7, 6.9 Hz, 6H). 200 H-58

2-([5-(3-Ethoxy-5-methoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid XSelect: 52% ACN up to 71% in 7 min LC-MS: (ES, m/z): 469. ¹H-NMR:(DMSO, ppm): δ: 12.63 (s, 1H), 7.24 (ddd, J = 8.6, 7.4, 1.7 Hz, 1H),6.98 (dd, J = 8.3, 1.0 Hz, 1H), 6.87 (td, J = 7.5, 1.0 Hz, 1H), 6.67(dd, J = 7.5, 1.6 Hz, 1H), 6.54-6.40 (m, 4H), 5.27 (s, 2H), 4.41 (s,2H), 3.96 (dq, J = 28.8, 7.0 Hz, 4H), 3.67 (s, 3H), 1.40 (s, 6H), 1.25(td, J = 6.9, 4.8 Hz, 6H). 201 H-59

2-([5-(3-Cyclopropoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXBridge: 42% ACN up to 75% in 7 min LC-MS: (ES, m/z): 451. ¹H NMR (300MHz, DMSO-d₆) δ 12.68 (s, 1H), 7.35 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H),7.29-7.17 (m, 1H), 7.01 (tdd, J = 13.0, 8.6, 1.4 Hz, 4H), 6.87 (td, J =7.5, 1.1 Hz, 1H), 6.68 (dd, J = 7.6, 1.7 Hz, 1H), 6.43 (s, 1H), 5.27 (s,2H), 4.42 (s, 2H), 4.00 (q, J = 6.9 Hz, 2H), 3.69 (tt, J = 6.3, 3.1 Hz,1H), 1.40 (s, 6H), 1.23 (t, J = 6.9 Hz, 3H), 0.71-0.51 (m, 4H). 202H-150

2-([5-(3-Cyclopropoxyphenyl)-1-[[2- (pyrrolidin-1-yl)phenyl]methyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XBridge: 28% ACN up to 58%in 7 min LC-MS: (ES, m/z): 476.15. ¹H NMR: (400 MHz, DMSO) δ 7.31 (t, J= 7.9, 7.9 Hz, 1H), 7.15 (m, 1H), 7.00 (m, 2H), 6.94 (m, 2H), 6.85 (t, J= 7.6, 7.6 Hz, 1H), 6.60 (dd, J = 7.6, 1.8 Hz, 1H), 6.46 (s, 1H), 5.31(s, 2H), 4.45 (s, 2H), 3.64 (m, 1H), 3.03 (m, 4H), 1.84 (m, 4H), 1.39(s, 6H), 0.60 (dq, J = 5.3, 3.2, 2.4, 2.4 Hz, 2H), 0.55 (dq, J = 7.8,3.6, 3.6, 3.4 Hz, 2H). 203 H-60

2-([1-[(2-Chlorophenyl)methyl]-5-(2,3- dihydro-1,4-benzodioxin-6-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XBridge: 45% ACN up to 58%in 7 min LC-MS: (ES, m/z): 443. ¹H NMR: (300 MHz, MeOD) δ 7.39 (m, 1H),7.25 (tt, J = 7.4, 7.4, 5.6, 5.6 Hz, 2H), 6.85 (m, 1H), 6.77 (d, J = 7.8Hz, 2H), 6.68 (m, 1H), 6.46 (s, 1H), 5.40 (s, 2H), 4.56 (s, 2H), 4.24(q, J = 1.1, 1.0, 1.0 Hz, 4H), 1.51 (s, 6H). 204 H-61

[[5-(2H-1,3-Benzodioxol-5-yl)-1-[(2- chlorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XBridge: 45% ACN up to 60% in 7 minLC-MS: (ES, m/z): 429. ¹H NMR: (DMSO) δ: 12.67 (s, 1H), 7.49- 7.38 (m,1H), 7.36-7.21 (m, 2H), 7.00-6.91 (m, 2H), 6.83 (dd, J = 7.9, 1.8 Hz,1H), 6.76-6.66 (m, 1H), 6.37 (s, 1H), 6.05 (s, 2H), 5.35 (s, 2H), 4.39(s, 2H), 1.38 (s, 6H) 205 H-62

2-([1-[(2-Chlorophenyl)methyl]-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXBridge: 25% ACN up to 52% in 7 min ¹H NMR (DMSO) δ: 7.93 (s, 1H), 7.55-7.46 (m, 2H), 7.29 (dtd, J = 21.6, 7.5, 1.6 Hz, 2H), 6.59 (dd, J = 7.6,1.7 Hz, 1H), 6.43 (s, 1H), 5.43 (s, 2H), 4.38 (s, 2H), 3.83 (s, 3H),1.39 (s, 6H) 206 H-21

2-([1-[(2-Chlorophenyl)methyl]-5-(1-methyl-1H-indol-6-yl)-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXSelect: 45% ACN up to 80% in 7 min LC-MS: (ES, m/z): 437. ¹H NMR: (300MHz, DMSO-d₆) δ 12.68 (s, 1H), 7.57 (dd, J = 8.2, 0.7 Hz, 1H), 7.48-7.36(m, 3H), 7.34-7.26 (m, 2H), 7.01 (dd, J = 8.2, 1.5 Hz, 1H), 6.83-6.75(m, 1H), 6.51-6.42 (m, 2H), 5.42 (s, 2H), 4.43 (s, 2H), 3.72 (s, 3H),1.41 (s, 6H). 207 H-22

2-([1-[(2-Ethoxyphenyl)methyl]-5-(1-methyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXSelect: 37% ACN up to 65% in 7 min LC-MS: (ES, m/z): 449. ¹H NMR: (300MHz, DMSO-d₆) δ 12.68 (s, 1H), 8.07 (d, J = 1.0 Hz, 1H), 7.78 (d, J =8.3 Hz, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.29-7.10 (m, 2H), 7.01-6.81 (m,2H), 6.74 (dd, J = 7.6, 1.7 Hz, 1H), 6.48 (s, 1H), 5.31 (s, 2H), 4.43(s, 2H), 4.00 (s, 3H), 3.91 (q, J = 6.9 Hz, 2H), 1.40 (s, 6H), 1.11 (t,J = 6.9 Hz, 3H). 208 H-63

2-([5-(3,5-Diethoxyphenyl)-1-[(2- ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XBridge: 45% ACN up to 80% in 7 minLC-MS: (ES, m/z): 483.15. ¹H NMR (300 MHz, DMSO) δ 7.22 (m, 1H), 6.97(m, 1H), 6.86 (td, J = 7.4, 7.4, 1.1 Hz, 1H), 6.66 (dd, J = 7.6, 1.7 Hz,1H), 6.45 (m, 3H), 6.42 (s, 1H), 5.26 (s, 2H), 4.40 (s, 2H), 4.00 (q, J= 7.0, 6.9, 6.9 Hz, 2H), 3.90 (q, J = 7.0, 7.0, 7.0 Hz, 4H), 1.39 (s,6H), 1.24 (td, J = 7.0, 7.0, 2.6 Hz, 9H). 209 H-66

2-([1-[(2-Chlorophenyl)methyl]-5-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXSelect: 35% ACN up to 65% in 7 min LC-MS: (ES, m/z): 439. ¹H NMR: (300MHz, DMSO-d₆) δ 12.71 (s, 1H), 8.07 (d, J = 0.9 Hz, 1H), 7.79 (d, J =1.4 Hz, 1H), 7.70 (dt, J = 8.8, 1.0 Hz, 1H), 7.49-7.36 (m, 2H),7.32-7.22 (m, 2H), 6.76 (dd, J = 5.7, 3.7 Hz, 1H), 6.44 (s, 1H), 5.39(s, 2H), 4.42 (s, 2H), 4.05 (s, 3H), 1.39 (s, 6H). 210 H-67

2-([5-(3-cyclobutoxyphenyl)-1-[(2- ethoxyphenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XBridge: 50% ACN up to 80% in 7 minLC-MS: (ES, m/z): 465. ¹H NMR: (300 MHz, DMSO-d₆) δ 12.68 (s, 1H),7.38-7.20 (m, 2H), 7.05-6.94 (m, 2H), 6.92-6.82 (m, 2H), 6.75- 6.62 (m,2H), 6.42 (s, 1H), 5.26 (s, 2H), 4.50 (q, J = 7.1 Hz, 1H), 4.42 (s, 2H),4.02 (q, J = 6.9 Hz, 2H), 2.30-2.15 (m, 2H), 2.03-1.86 (m, 2H),1.79-1.65 (m, 1H), 1.63-1.47 (m, 1H), 1.40 (s, 6H), 1.24 (t, J = 6.9 Hz,3H). 211 H-71

2-([5-(3,5-Dimethoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXBridge: 40% ACN up to 68% in 7 min LC-MS: (ES, m/z): 455. ¹H NMR: (300MHz, MeOH-d₄) δ 7.24 (td, J = 7.8, 7.4, 1.7 Hz, 1H), 6.99-6.81 (m, 2H),6.69 (dd, J = 7.6, 1.6 Hz, 1H), 6.54-6.41 (m, 4H), 5.33 (s, 2H), 4.57(s, 2H), 4.04 (q, J = 7.0 Hz, 2H), 3.64 (s, 6H), 1.52 (s, 6H), 1.34 (t,J = 7.0 Hz, 3H). 212 H-23

2-([5-(3,5-Dimethoxyphenyl)-1-(2- phenylethyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 40% ACN up to 66% in 7 min LC-MS: (ES,m/z): 425. ¹H NMR: (300 MHz, DMSO-d₆) δ 12.67 (s, 1H), 7.32-7.11 (m,3H), 7.06-6.92 (m, 2H), 6.53 (t, J = 2.3 Hz, 1H), 6.37 (d, J = 2.3 Hz,2H), 6.26 (s, 1H), 4.43 (s, 2H), 4.34-4.20 (m, 2H), 3.74 (s, 6H),3.13-2.99 (m, 2H), 1.41 (s, 6H). 213 H-74

2-([1-[(2-Chlorophenyl)methyl]-5-(3,5- diethoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XSelect: 53% ACN up to 76% in 7 minLC-MS: (ES, m/z): 473.10. ¹H NMR: (300 MHz, DMSO) δ 12.63 (s, 1H), 7.45(m, 1H), 7.30 (m, 2H), 6.72 (m, 1H), 6.45 (m, 4H), 5.38 (s, 2H), 4.41(s, 2H), 3.91 (q, J = 7.0, 7.0, 7.0 Hz, 4H), 1.39 (s, 6H), 1.24 (t, J =6.9, 6.9 Hz, 6H). 214 H-111

2-([5-(3-Cyclopropoxyphenyl)-1-[[2- (dimethylamino)phenyl]methyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XSelect: 67% ACN up to 68%in 7 min LC-MS: (ES, m/z): 450. ¹H-NMR: (CDCl3, ppm): ¹H NMR (300 MHz,MeOD) δ 7.25 (m, 2H), 7.17 (dd, J = 8.1, 1.4 Hz, 1H), 7.00 (m, 2H), 6.90(m, 2H), 6.74 (dd, J = 7.6, 1.5 Hz, 1H), 6.51 (s, 1H), 5.43 (s, 2H),4.59 (s, 2H), 3.55 (m, 1H), 2.60 (s, 6H), 1.53 (s, 6H), 0.59 (m, 4H).215 H-99

2-([5-(3-Methoxyphenyl)-1-[2-(propan- 2-yloxy)phenyl]-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 38% ACN up to 61% in 7 minLC-MS: (ES, m/z): 425. ¹H NMR (300 MHz, DMSO) δ 7.46 (m, 1H), 7.38 (t, J= 7.9, 7.9 Hz, 1H), 7.18 (t, J = 7.9, 7.9 Hz, 1H), 7.03 (m, 2H), 6.81(m, 2H), 6.68 (m, 1H), 6.58 (s, 1H), 4.45 (s, 2H), 4.34 (m, 1H), 3.57(s, 3H), 1.41 (s, 6H), 0.96 (s, 3H), 0.59 (s, 3H). 216 H-96

2-Methyl-2-([5-[3-(2-methylpropoxy)- phenyl]-1-phenyl-1H-pyrazol-3-yl]-methoxy)propanoic acid SunFire: 69% ACN up to to 71% ACN in 8 min LC-MS:(ES, m/z): 409. H-NMR: (MeOD, ppm): δ: 7.48-7.32 (m, 3H), 7.35-7.14 (m,3H), 6.91- 6.78 (m, 2H), 6.73-6.63 (m, 2H), 4.61 (s, 2H), 3.54 (d, J =6.5 Hz, 2H), 1.92 (hept, J = 6.7 Hz, 1H), 1.53 (s, 6H), 0.95 (d, J = 6.7Hz, 6H). 217 H-122

(2R)-2-([5-(3-cyclopropoxyphenyl)-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3- yl]methoxy)-2-methylbutanoic acidXSelect 43% ACN up to 65% in 7 min LC-MS: (ES, m/z): 461. ¹H NMR: (300MHz, DMSO-d₆) ¹ δ: 12.67 (s, 2H), 8.18 (s, 1H), 7.91 (d, J = 8.0 Hz,2H), 7.37 (d, J = 7.3 Hz, 2H), 7.28-7.12 (m, 4H), 7.03-6.75 (m, 8H),4.53 (s, 4H), 3.45 (s, 7H), 2.49 (s, 1H), 1.76 (dh, J = 14.3, 7.2 Hz,4H), 1.40 (s, 5H), 0.88 (t, J = 7.4 Hz, 6H), 0.50-0.35 (m, 8H). 218H-123

(2S)-2-([1-[(2-chlorophenyl)methyl]-5- (3-methoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid XSelect: 67% ACN up to 68% in 7 min)LC-MS: (ES, m/z): 429. ¹H NMR (DMSO) δ: 12.64 (s, 1H), 7.50- 7.22 (m,4H), 7.02-6.84 (m, 3H), 6.78-6.69 (m, 1H), 6.45 (s, 1H), 5.38 (s, 2H),4.41 (d, J = 1.9 Hz, 2H), 3.69 (s, 3H), 1.84-1.60 (m, J = 7.1 Hz, 2H),1.36 (s, 3H), 0.85 (t, J = 7.4 Hz, 3H). 219 H-124

(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(3-methoxyphenyl)-1H-pyrazol-3-yl]- methoxy)-2-methylbutanoic acidXBridge: 40% ACN up to 75% in 7 min LC-MS: (ES, m/z): 429. ¹H NMR: (400MHz, DMSO-d₆) δ 12.61 (s, 1H), 7.49-7.22 (m, 4H), 7.02-6.84 (m, 3H),6.78-6.69 (m, 1H), 6.46 (s, 1H), 5.38 (s, 2H), 4.41 (d, J = 2.2 Hz, 2H),3.69 (s, 3H), 1.84-1.61 (m, J = 7.6 Hz, 2H), 1.36 (s, 3H), 0.85 (t, J =7.4 Hz, 3H) 220 H-130

(2R)-2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylbutanoicacid XSelect: 48% ACN up to 67% in 7 min LC-MS: (ES, m/z): 467. ¹H NMR:(300 MHz, DMSO-d₆) ¹ δ: 12.63 (s, 1H), 8.08 (s, 1H), 7.79 (d, J = 8.4Hz, 1H), 7.68 (s, 1H), 7.46-7.37 (m, 1H), 7.29 (q, J = 4.8 Hz, 2H), 7.13(d, J = 8.4 Hz, 1H), 6.84-6.74 (m, 1H), 6.53 (s, 1H), 5.46 (s, 2H),4.52-4.32 (m, 4H), 1.75 (hept, J = 7.0 Hz, 2H), 1.41-1.26 (m, 6H), 0.86(t, J = 7.4 Hz, 3H). 221 H-142

2-([5-(3-Cyclopropoxyphenyl)-1-[2-(pyrrolidin-1-yl)phenyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid XBridge: 45% ACN up to 77% in 7 min LC-MS: (ES, m/z): 462.1. ¹HNMR: (300 MHz, DMSO) δ 7.22 (m, 2H), 7.03 (dd, J = 7.7, 1.7 Hz, 1H),6.93 (m, 2H), 6.86 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H), 6.74 (dd, J = 8.5,1.3 Hz, 1H), 6.67 (td, J = 7.5, 7.5, 1.2 Hz, 1H), 6.63 (s, 1H), 4.47 (s,2H), 3.51 (tt, J = 6.1, 6.1, 3.0, 3.0 Hz, 1H), 2.75 (qq, J = 8.5, 8.5,8.5, 5.0, 5.0, 4.6 Hz, 4H), 1.64 (m, 4H), 1.41 (s, 6H), 0.62 (m, 2H),0.50 (m, 2H). 222 H-129

(2R)-2-([1-(2-Chlorophenyl)-5-(3,5- dimethoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylbutanoic acid XSelect: 45% ACN up to 64% in 7 minLC-MS: (ES, m/z): 445. ¹H NMR: (300 MHz, DMSO-d₆) δ 12.67 (s, 1H),7.74-7.38 (m, 4H), 6.71 (s, 1H), 6.41 (t, J = 2.2 Hz, 1H), 6.32 (d, J =2.2 Hz, 2H), 4.47 (d, J = 2.0 Hz, 2H), 3.60 (s, 6H), 1.77 (hept, J = 7.0Hz, 2H), 1.39 (s, 3H), 0.88 (t, J = 7.4 Hz, 3H). 223 H-126

(2R)-2-([5-[3-(2,2-Dimethyl- propoxy)phenyl]-1-(1-methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)- 2-methylbutanoic acid XSelect:55% ACN up to 81% in 7 min LC-MS: (ES, m/z): 491. ¹H NMR: (300 MHz,DMSO-d₆) δ 12.70 (s, 1H), 8.20 (s, 1H), 7.92 (dd, J = 8.1, 1.0 Hz, 1H),7.41 (dd, J = 7.3, 1.0 Hz, 1H), 7.29-7.04 (m, 2H), 6.92-6.75 (m, 3H),6.63 (dd, J = 2.5, 1.6 Hz, 1H), 4.54 (s, 2H), 3.44 (s, 3H), 3.19 (s,2H), 1.91-1.69 (m, 2H), 1.41 (s, 3H), 0.89 (d, J = 4.1 Hz, 12H). 224H-107

2-([1-[(2-Chlorophenyl)methyl]-5-(3,5-dimethoxyphenyl)-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXBridge: 45% ACN up to 65% in 7 min LC-MS: (ES, m/z): 445. ¹H-NMR:(MeOD): δ: 7.46-7.36 (m, 1H), 7.35-7.21 (m, 2H), 6.80-6.71 (m, 1H),6.58-6.39 (m, 4H), 5.43 (s, 2H), 4.58 (s, 2H), 3.66 (s, 6H), 1.52 (s,6H). 225 H-112

2-([5-(3-Cyclopropoxyphenyl)-1-[2- (dimethylamino)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 64% ACN up to 78% in 7 minLC-MS: (ES, m/z): 436. ¹H-NMR: (MeOD, ppm): δ: 7.47-7.29 (m, 2H),7.26-7.06 (m, 3H), 6.96- 6.81 (m, 3H), 6.71 (s, 1H), 4.63 (s, 2H), 3.50(tt, J = 6.2, 3.0 Hz, 1H), 2.44 (s, 6H), 1.54 (s, 6H), 0.70-0.47 (m,4H). 226 H-108

2-([1-[(2-Chlorophenyl)methyl]-5-(1-methyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXBridge: 38% ACN up to 61% in 7 min LC-MS: (ES, m/z): 439. ¹H NMR: (300MHz, MeOH-d₄) δ 8.02 (d, J = 1.0 Hz, 1H), 7.77 (dd, J = 8.4, 0.9 Hz,1H), 7.46 (q, J = 1.1 Hz, 1H), 7.43-7.32 (m, 1H), 7.32-7.20 (m, 2H),7.13 (dd, J = 8.4, 1.4 Hz, 1H), 6.95-6.77 (m, 1H), 6.64 (s, 1H), 5.49(s, 2H), 4.61 (s, 2H), 3.97 (s, 3H), 1.53 (s, 6H). 227 H-109

2-([1-[(2-Chlorophenyl)methyl]-5-[2-(propan-2-yloxy)-1,3-oxazol-5-yl]-1H- pyrazol-3-yl]methoxy)-2-methylpropanoic acid XBridge: 35% ACN up to 50% in 7 min LC-MS: (ES,m/z): 434. ¹H NMR (400 MHz, DMSO-d₆) δ 7.59 (s, 1H), 7.49 (dd, J = 7.7,1.6 Hz, 1H), 7.31 (dtd, J = 16.7, 7.5, 1.7 Hz, 2H), 6.78 (dd, J = 7.5,1.9 Hz, 1H), 6.54 (s, 1H), 5.50 (s, 2H), 4.37 (s, 2H), 4.11 (p, J = 6.7Hz, 1H), 1.38 (s, 6H), 1.26 (d, J = 6.7 Hz, 6H). 228 H-133

2-([1-[2-(Azetidin-1-yl)phenyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXSelect: 38% ACN up to 64% in 7 min LC-MS: (ES, m/z): 460.15. ¹H NMR(300 MHz, DMSO) δ 7.99 (d, J = 0.9 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H),7.54 (d, J = 1.3 Hz, 1H), 7.27 (ddd, J = 8.5, 7.4, 1.6 Hz, 1H), 7.09(ddd, J = 20.0, 8.1, 1.5 Hz, 2H), 6.71 (m, 2H), 6.49 (dd, J = 8.2, 1.3Hz, 1H), 4.49 (s, 2H), 4.28 (q, J = 7.2, 7.2, 7.2 Hz, 2H), 3.47 (dt, J =11.8, 7.3, 7.3 Hz, 4H), 2.05 (m, 2H), 1.43 (s, 6H), 1.23 (t, J = 7.1,7.1 Hz, 3H). 229 H-135

2-([5-(1-ethyl-1H-indazol-6-yl)-1-[2-(pyrrolidin-1-yl)phenyl]-1H-pyrazol-3- yl]methoxy)-2-methylpropanoicacid XSelect: 52% ACN up to 78% in 7 min LC-MS: (ES, m/z): 474. ¹H NMR(300 MHz, DMSO) δ 12.66 (s, 1H), 7.98 (d, J = 1.0 Hz, 1H), 7.63 (d, J =8.4 Hz, 1H), 7.43 (d, J = 1.4 Hz, 1H), 7.25 (ddd, J = 8.6, 7.2, 1.7 Hz,1H), 7.07 (ddd, J = 8.4, 5.7, 1.5 Hz, 2H), 6.72 (m, 3H), 4.50 (s, 2H),4.25 (q, J = 7.2, 7.2, 7.2 Hz, 2H), 2.77 (m, 4H), 1.70 (m, 2H), 1.60 (m,2H), 1.43 (s, 6H), 1.22 (t, J = 7.2, 7.2 Hz, 3H). 230 H-136

2-Methyl-2-([5-(1-methyl-1H-indazol-6-yl)-1-[2-(pyrrolidin-1-yl)phenyl]-1H- pyrazol-3-yl]methoxy]propanoicacid XBridge: 18% ACN up to 39% in 7 min LC-MS: (ES, m/z): 460. ¹H NMR:(300 MHz, DMSO-d₆) δ 7.97 (d, J = 0.9 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H),7.47 (s, 1H), 7.25 (ddd, J = 8.6, 7.2, 1.7 Hz, 1H), 7.14-6.94 (m, 2H),6.82- 6.57 (m, 3H), 4.50 (s, 2H), 3.88 (s, 3H), 2.77 (q, J = 6.0, 4.4Hz, 4H), 1.84-1.48 (m, 4H), 1.40 (s, 6H). 231 H-137

2-([5-(3,5-Dimethoxyphenyl)-1-[2- (pyrrolidin-1-yl)phenyl]-1H-pyrazol-3-yl] methoxy)-2-methylpropanoic acid XSelect: 42% ACN up to 75% in 7 minLC-MS: (ES, m/z): 466. H NMR: (300 MHz, DMSO-d6) δ 12.59 (s, 1H), 7.25(ddd, J = 8.7,7.2, 1.7 Hz, 1H), 7.00 (dd, J = 7.7, 1.7 Hz, 1H), 6.80-6.72 (m, 1H), 6.71-6.62 (m, 2H), 6.42 (d, J = 2.3 Hz, 2H), 6.37 (t, J =2.2 Hz, 1H), 4.46 (s, 2H), 2.79 (t, J = 5.5 Hz, 4H), 1.79-1.55 (m, 4H),1.41 (s, 6H). 232 H-143

2-([1-[2-(Azetidin-1-yl)phenyl]-5-(3-cyclopropoxyphenyl)-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXSelect: 57% ACN up to 67% in 7 min \LC-MS: (ES, m/z): 448.3. ¹H NMR:(300 MHz, MeOD) δ 7.29 (ddd, J = 8.2, 7.3, 1.6 Hz, 1H), 7.20 (m, 1H),7.05 (dd, J = 7.3, 1.6 Hz, 3H), 6.89 (m, 1H), 6.74 (td, J = 7.6, 7.6,1.3 Hz, 1H), 6.69 (s, 1H), 6.54 (dd, J = 8.2, 1.3 Hz, 1H), 4.59 (s, 2H),3.49 (m, 5H), 2.13 (m, 2H), 1.53 (s, 6H), 0.66 (q, J = 5.7, 5.0, 5.0 Hz,2H), 0.56 (tt, J = 6.0, 6.0, 3.1, 3.1 Hz, 2H). 233 H-144

2-([5-(3-Cyclopropoxyphenyl)-1-[2-[(3S)-3-hydroxypyrrolidin-1-yl]phenyl]- 1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 36% ACN up to 64% in 7 min LC-MS: (ES,m/z): 478. ¹H NMR (300 MHz, DMSO) δ 7.22 (m, 2H), 7.02 (m, 2H), 6.89 (m,2H), 6.73 (m, 1H), 6.63 (dd, J = 16.0, 5.1 Hz, 2H), 4.47 (m, 2H), 4.10(m, 1H), 3.52 (dp, J = 8.9, 3.1, 3.1, 3.0, 3.0 Hz, 1H), 3.08 (q, J =8.8, 8.8, 8.6 Hz, 1H), 2.95 (dt, J = 9.1, 4.4, 4.4 Hz, 1H), 2.86 (dt, J= 10.0, 4.7, 4.7 Hz, 1H), 2.74 (dt, J = 9.2, 5.4, 5.4 Hz, 1H), 2.63(ddd, J = 11.3, 5.4, 2.6 Hz, 1H), 1.78 (ddd, J = 12.9, 8.4, 4.8 Hz, 1H),1.64 (m, 1H), 1.41 (d, J = 2.2 Hz, 6H), 0.62 (q, J = 7.7, 6.1, 6.1 Hz,2H), 0.48 (dq, J = 8.5, 3.2, 3.2, 3.2 Hz, 2H). 234 H-145

2-([5-(3-Cyclopropoxyphenyl)-1-[2- (morpholin-4-yl)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XBridge: 40% ACN up to 65% in 7 minLC-MS: (ES, m/z): 478.1. 1H NMR: (300 MHz, DMSO) δ 7.50 (dd, J = 7.8,1.6 Hz, 1H), 7.39 (td, J = 7.7, 7.7, 1.7 Hz, 1H), 7.19 (dd, J = 8.4, 7.1Hz, 2H), 6.93 (m, 2H), 6.83 (m, 2H), 6.69 (s, 1H), 4.48 (s, 2H), 3.49(tt, J = 5.9, 5.9, 3.3, 3.3 Hz, 1H), 3.32 (dd, J = 9.8, 5.7 Hz, 2H),3.11 (m, 2H), 2.39 (d, J = 12.6 Hz, 2H), 2.15 (m, 2H), 1.41 (s, 6H),0.52 (m, 4H). 235 H-146

2-([5-(3-Cyclopropoxyphenyl)-1-[2-(2-oxopyrrolidin-1-yl)phenyl]-1H-pyrazol- 3-yl]methoxy)-2-methylpropanoicacid XSelect: 33% ACN up to 58% in 7 min LC-MS: (ES, m/z): 476.10. ¹HNMR (300 MHz, DMSO) δ 12.65 (s, 1H), 7.45 (m, 2H), 7.31 (m, 1H), 7.22(t, J = 7.9, 7.9 Hz, 1H), 7.12 (m, 1H), 7.06 (m, 1H), 7.01 (dt, J = 7.6,1.2, 1.2 Hz, 1H), 6.88 (ddd, J = 8.3, 2.5, 1.0 Hz, 1H), 6.57 (s, 1H),4.45 (s, 2H), 3.56 (tt, J = 6.1, 6.1, 3.0, 3.0 Hz, 1H), 3.38 (t, J = 6Hz, 2H), 2.11 (t, J = 7.9, 7.9 Hz, 2H), 1.92 (p, J = 7.4, 7.4, 7.2, 7.2Hz, 2H), 1.41 (s, 6H), 0.54 (m, 2H), 0.44 (m, 2H). 236 H-147

2-([5-(3-Cyclopropoxyphenyl)-1-[2-(1H-pyrazol-1-yl)phenyl]-1H-pyrazol-3-yl]- methoxy)-2-methylpropanoic acidXSelect: 38% ACN up to 65% in 7 min LC-MS: (ES, m/z): 459.15. ¹H NMR(300 MHz, DMSO) δ 7.63 (m, 3H), 7.52 (m, 2H), 7.09 (t, J = 7.9, 7.9 Hz,1H), 6.83 (m, 2H), 6.63 (dd, J = 2.5, 1.5 Hz, 1H), 6.56 (m, 2H), 6.28(dd, J = 2.5, 1.8 Hz, 1H), 4.48 (s, 2H), 3.52 (dt, J = 6.0, 3.1, 3.1 Hz,1H), 1.41 (s, 6H), 0.61 (m, 2H), 0.47 (m, 2H). 237 H-148

2-([5-(3-Cyclopropoxyphenyl)-1-[2-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]- 1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 37% ACN up to 64% in 7 min LC-MS: (ES,m/z): 478.15. ¹H NMR (300 MHz, DMSO) δ 7.22 (m, 2H), 7.02 (m, 2H), 6.90(m, 2H), 6.74 (m, 1H), 6.63 (m, 2H), 4.46 (m, 2H), 4.10 (p, J = 5.2,5.2, 4.5, 4.5 Hz, 1H), 3.52(m, 1H), 3.06 (p, J = 8.4, 8.4, 8.2, 8.2 Hz,1H), 2.95 (td, J = 9.0, 8.5, 4.0 Hz, 1H), 2.86 (dt, J = 9.9, 4.7, 4.7Hz, 1H), 2.74 (dt, J = 9.3, 5.4, 5.4 Hz, 1H), 2.63 (ddd, J = 10.6, 5.9,2.5 Hz, 1H), 1.78 (ddd, J = 12.8, 8.3, 4.8 Hz, 1H), 1.64 (dd, J =7.7,4.1 Hz, 1H), 1.41 (d, J = 2.2 Hz, 6H), 0.61 (dd, J = 9.2, 4.6 Hz,2H), 0.48 (dq, J = 10.3, 3.1, 2.7, 2.7 Hz, 2H). 238 H-151

2-([5-(3-Cyclobutoxyphenyl)-1-[[2- (pyrrolidin-1-yl)phenyl]methyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XSelect: 60% ACN up to 95%in 7 min LC-MS: (ES, m/z): 490. ¹H NMR: (300 MHz, DMSO-d₆) δ 12.67 (s,1H), 7.29 (t, J = 8.0 Hz, 1H), 7.19 (ddd, J = 8.7, 7.2, 1.6 Hz, 1H),7.06 (dd, J = 8.2, 1.2 Hz, 1H), 6.97-6.80 (m, 3H), 6.64-6.54 (m, 2H),6.45 (s, 1H), 5.30 (s, 2H), 4.44 (s, 2H), 4.41 (d, J = 7.1 Hz, 1H),3.19-2.87 (m, 4H), 2.26- 2.07 (m, 2H), 1.99-1.88 (m, 2H), 1.88- 1.80 (m,4H), 1.71 (q, J = 10.1 Hz, 1H), 1.62-1.46 (m, 1H), 1.41 (s, 6H), 1.20(s, 1H). 239 H-156

2-([1-(2-Cyanophenyl)-5-(3-cyclo- propoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid XBridge: 35% ACN up to 64% in 7 minLC-MS: (ES, m/z): 418. ¹H-NMR: (DMSO, ppm): ¹H NMR (300 MHz, DMSO-d₆) δ12.73 (s, 1H), 7.99 (dd, J = 7.7, 1.5 Hz, 1H), 7.83 (td, J = 7.8, 1.6Hz, 1H), 7.73-7.52 (m, 2H), 7.27 (t, J = 7.9 Hz, 1H), 6.97 (ddd, J =8.3, 2.5, 1.0 Hz, 1H), 6.91-6.79 (m, 2H), 6.75 (s, 1H), 4.52 (s, 2H),3.64 (tt, J = 6.1, 3.0 Hz, 1H), 1.44 (s, 6H), 0.70- 0.44 (m, 4H). 240

2-([5-(3,5-Dimethoxyphenyl)-1-phenyl- 1H-pyrazol-3-yl]methoxy)-2-methyl-propanoic acid LC-MS (ES, m/z): 395. ¹H NMR (CDCl₃): δ 1.61 (s, 6H),3.66 (s, 6H), 4.69 (s, 2H), 6.37 (d, J = 2.30, 2H), 6.41-6.44 (m, 1H),6.55(s, 1H), 7.30- 7.40 (m, 5H). 241

2-([5-(3,5-Dimethoxyphenyl)-1-(3- chlorophenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 431. ¹H NMR (CDCl₃): δ1.59 (s, 6H), 3.68 (s, 6H), 4.65 (s, 2H), 6.35 (d, J = 2.15 hZ, 2H),6.40-6.46 (m, 1H), 6.53 (s, 1H), 7.08-7.14 (m, 1H), 7.19-7.31 (m, 2H),7.39-7.44 (m, 1H). 242

2-([5-(3,5-Dimethoxyphenyl)-1-(3- methoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 427. ¹H NMR (CDCl₃): δ1.59 (s, 6H), 3.66 (s, 6H), 3.73 (s, 3H), 4.66 (s, 2H), 6.36 (d, J =2.25 Hz, 2H), 6.41 (t, J = 2.21 Hz, 1H), 6.79-6.95 (m, 3H), 7.21 (t, J =8.10 Hz, 1H). 243

2-([5-(3,5-Dimethoxyphenyl)-1-(3- ethoxyphenyl)-1H-pyrazol-3-yl]-methoxy)-2-methylpropanoic acid LC-MS (ES m/z): 441. ¹H NMR (CDCl₃): δ1.33 (t, J = 7.00 Hz, 3H), 1.54 (s, 6H), 3.63 (s, 6H), 3.92 (q, J = 7.00Hz, 2H), 4.63 (s, 2H), 6.34-6.38 (m, 3H), 6.48 (s, 1H), 6.81-6.88 (m,3H), 7.16 (t, J = 8.00 Hz, 1H). 244

2-([5-(3,5-Dimethoxyphenyl)-1-[3- (dimethylamino)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 441. ¹H NMR (CDCl₃):δ 1.51 (s, 6H), 2.85 (s, 6H), 3.62 (s, 6H), 4.58 (s, 2H), 6.38- 6.41 (m,3H), 6.54-6.6.57 (m, 1H), 6.61(s, 1H), 7.74-6.76 (m, 1H), 7.20 (t, J =8.11 Hz, 1H). 245

2-([5-(3,5-Dimethoxyphenyl)-1-[2- (dimethylamino)phenyl]-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid LC-MS (ES, m/z): 440. ¹H NMR (CDCl₃):δ 1.52 (s, 6H), 2.23 (s, 6H), 3.57 (s, 6H), 4.60 (s, 2H), 6.31- 6.36 (m,3H), 6.67 (s, 1H), 6.91 (d, J = 8.00 Hz, 1H), 7.03-7.04 (m, 1H), 7.33-7.38 (m, 2H). 246 H-139

2-([1-[2-(Azetidin-1-yl)phenyl]-5-(1-propyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylpropanoic acidXSelect: 40% ACN up to 70% in 7 min LC-MS: (ES, m/z): 474.10 ¹H NMR (300MHz, MeOD) δ 7.96 (d, J = 0.9 Hz, 1H), 7.71 (dd, J = 8.5, 0.8 Hz, 1H),7.42 (s, 1H), 7.31 (m, 2H), 7.13 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 13.8Hz, 2H), 6.56 (d, J = 8.2 Hz, 1H), 4.63 (s, 2H), 4.17 (t, J = 7.0, 7.0Hz, 2H), 3.57 (m, 4H), 2.14 (q, J = 7.2, 7.2, 7.2 Hz, 2H), 1.69 (q, J =7.2, 7.2, 7.2 Hz, 2H), 1.54 (s, 6H), 0.79 (t, J = 7.4, 7.4 Hz, 3H). 247H-70

2-Methyl-2-([5-[3-(2-methylpropoxy)-phenyl]-1-([pyridin-2-yl]methyl)-1H- pyrazol-3-yl]methoxy)propanoic acidXSelect: 40% ACN up to 70% in 7 min LC-MS: (ES, m/z): 424. ¹H NMR (300MHz, Methanol-d₄) δ 8.70 (ddd, J = 5.5, 1.7, 0.8 Hz, 1H), 8.27 (td, J =7.9, 1.7 Hz, 1H), 7.75 (ddd, J = 7.7, 5.5, 1.2 Hz, 1H), 7.51-7.31 (m,2H), 7.15-6.88 (m, 3H), 6.57 (s, 1H), 5.65 (s, 2H), 4.58 (s, 2H), 3.71(d, J = 6.5 Hz, 2H), 2.04 (dq, J = 13.2, 6.6 Hz, 1H), 1.52 (s, 6H), 1.03(d, J = 6.7 Hz, 6H). 248 H-80

2-([1-[(2-Chlorophenyl)methyl]-5-(1- methyl-1H-1,3-benzodiazol-6-yl)-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XBridge: 20% ACN up to 34%in 7 min LC-MS: (ES, m/z): 438. ¹H NMR (DMSO-d₆) δ: 8.23 (s, 1H), 7.65(d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.47-7.36 (m, 1H), 7.34-7.20 (m, 2H),7.17 (d, J = 8.3 Hz, 1H), 6.83- 6.73 (m, 1H), 6.47 (s, 1H), 5.42 (s,2H), 4.46 (s, 2H), 3.78 (s, 3H), 1.36 (s, 6H). 249 H-33

2-([5-(3,5-Dimethoxyphenyl)-1-(1- methyl-1H-indazol-7-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 30% ACN up to 65% in 7 minLC-MS: (ES, m/z): 451. ¹H NMR (300 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.92(s, 1H), 7.44 (dd, J = 7.3, 1.0 Hz, 1H), 7.21 (s, 1H), 6.84 (s, 1H),6.35 (dt, J = 10.9, 2.2 Hz, 3H), 4.53 (s, 2H), 3.52 (s, 6H), 3.41 (s,3H), 1.44 (s, 6H). 250 H-14

2-Methyl-2-([5-(1-propyl-1H-indazol-6-yl)-1-[2-(pyrrolidin-1-yl)phenyl]-1H- pyrazol-3-yl]methoxy]propanoicacid XBridge: 10% ACN up to 50% in 7 min LC-MS: (ES, m/z): 488.2. ¹H NMR(300 MHz, DMSO-d₆) δ 7.98 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.37 (s,1H), 7.25 (m, 1H), 7.08 (t, J = 7.5, 7.5 Hz, 2H), 6.72 (m, 3H), 4.50 (s,2H), 4.14 (t, J = 7.1, 7.1 Hz, 2H), 2.77 (q, J = 6.4, 6.4, 5.2 Hz, 4H),1.63 (tt, J = 15.4, 15.4, 7.1, 7.1 Hz, 6H), 1.40 (s, 6H), 0.72 (t, J =7.4, 7.4 Hz, 3H). 251 H-138

2-((1-(2-( Azelidin-1-yl)phenyl)-5-(3,5- dimethoxyphenyl)-1H-pyrazol-3-yl)methoxy)-2-methylpropanoic acid XBridge: 25% ACN up to 37% in 7 minLC-MS: (ES, m/z): 452. ¹H NMR (300 MHz, DMSO-d₆) δ 7.26 (t, J = 7.4 Hz,1H), 6.95 (d, J = 7.5 Hz, 1H), 6.67 (q, J = 7.0, 6.0 Hz, 2H), 6.58- 6.43(m, 3H), 6.38 (t, J = 2.2 Hz, 1H), 4.47 (s, 2H), 3.59 (s, 6H), 3.45 (dq,J = 31.0, 7.3 Hz, 4H), 2.17-1.89 (m, 2H), 1.36 (s, 6H). 252 H-72

2-([5-(3,5-Dimethoxyphenyl)-1-[(2- ethoxy-6-fluorophenyl)methyl]-1H-pyrazol-3-yl]methoxy)-2- methylpropanoic acid XSelect: 42% ACN up to 72%in 7 min LC-MS: (ES, m/z): 473. ¹H NMR (300 MHz, DMSO-d₆) δ 7.27 (td, J= 8.4, 8.3, 6.9 Hz, 1H), 6.76 (dt, J = 8.8, 4.6, 4.6 Hz, 2H), 6.66 (d, J= 2.3 Hz, 2H), 6.57 (t, J = 2.2, 2.2 Hz, 1H), 6.25 (s, 1H), 5.26 (s,2H), 4.27 (s, 2H), 3.88 (q, J = 7.0, 7.0, 7.0 Hz, 2H), 3.78 (s, 6H),1.34 (s, 6H), 1.06 (d, J = 6.9, 6.9 Hz, 3H). 253 H-83

2-([5-[3-(2,2-Dimethylpropoxy)phenyl]- 1-(quinolin-8-yl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 50% ACN up to 80% in 7 minLC-MS: (ES, m/z): [M + 1] = 474. ¹H-NMR: (DMSO, ppm): δ: 8.77 (dd, J =4.2, 1.7 Hz, 1H), 8.46 (dd, J = 8.4, 1.7 Hz, 1H), 8.14 (dd, J = 8.2, 1.5Hz, 1H), 7.83 (dd, J = 7.4, 1.5 Hz, 1H), 7.70 (dd, J = 8.2, 7.3 Hz, 1H),7.55 (dd, J = 8.3, 4.2 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 6.79-6.60 (m,3H), 6.53 (dd, J = 2.6, 1.5 Hz, 1H), 4.49 (s, 2H), 3.02 (s, 2H), 1.43(s, 6H), 0.81 (s, 9H). 254 H-73

2-([5-(3,5-Dimethoxyphenyl)-1- ([pyridin-2-yl]methyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 25% ACN up to 56% in 7 minLC-MS: (ES, m/z): 412.05. ¹H NMR (300 MHz, DMSO) δ 12.62 (s, 1H), 8.52(ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.78 (td, J = 7.7, 7.7, 1.8 Hz, 1H),7.30 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.08 (dt, J = 7.8, 1.1, 1.1 Hz,1H), 6.70 (d, J = 2.3 Hz, 2H), 6.52 (t, J = 2.3, 2.3 Hz, 1H), 6.42 (s,1H), 5.37 (s, 2H), 4.38 (s, 2H), 3.70 (s, 6H), 1.38 (s, 6H). 255 H-35

2-([1-(1,3-Dimethyl-1H-indazol-7-yl)-5-[3-(2,2-dimethylpropoxy)phenyl]-1H- pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 50% ACN up to 80% in 7 min LC-MS: (ES,m/z): 405.35. ¹H NMR (300 MHz, DMSO) δ 12.60 (s, 1H), 7.83 (dd, J = 8.1,1.0 Hz, 1H), 7.34 (dd, J = 7.3, 0.9 Hz, 1H), 7.12 (m, 2H), 6.78 (m, 3H),6.60 (m, 1H), 4.52 (s, 2H), 3.33 (s, 3H), 3.14 (s, 2H), 2.46 (s, 3H),1.42 (s, 6H), 0.85 (s, 9H). 256 H-69

2-([5-[3-(2,2-Dimethylpropoxy)phenyl]-1-[(1-methyl-1H-indazol-7-yl)methyl]- 1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 60% ACN up to 70% in 7 min LC-MS: (ES,m/z): 491.25. ¹H NMR (400 MHz, DMSO) δ 8.03 (s, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.33 (t, J = 7.9, 7.9 Hz, 1H), 7.02 (m, 2H), 6.94 (dd, J = 8.3,2.4 Hz, 1H), 6.88 (s, 1H), 6.56 (d, J = 7.2 Hz, 1H), 6.51 (s, 1H), 5.95(s, 2H), 4.43 (s, 2H), 4.20 (s, 3H), 3.32 (s, 2H), 1.39 (s, 6H), 0.88(s, 9H). 257 H-131

(S)-2-((1-(2-chlorobenzyl)-5-(1-ethyl- 1H-indazol-6-yl)-1H-pyrazol-3-yl)methoxy)-2-methylbutanoic acid LC-MS: (ES, m/z): 467.10. ¹H NMR (300MHz, DMSO-d6) δ 12.64 (s, 1H), 8.07 (d, J = 0.9 Hz, 1H), 7.78 (dd, J =8.3, 0.8 Hz, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.49-7.34 (m, 1H), 7.36-7.18 (m, 2H), 7.11 (dd, J = 8.3, 1.3 Hz, 1H), 6.84-6.72 (m, 1H), 6.52(s, 1H), 5.45 (s, 2H), 4.43 (d, J = 2.2 Hz, 2H), 4.37 (q, J = 7.2 Hz,2H), 1.74 (hept, J = 7.0 Hz, 2H), 1.37 (s, 3H), 1.31 (t, J = 7.2 Hz,3H), 0.85 (t, J = 7.4 Hz, 3H). 258 H-36

2-([5-[3-(2,2-Dimethylpropoxy)phenyl]-1-(1-methyl-1H-1,2,3-benzotriazol-7-yl)- 1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 50% ACN up to 70% in 7 min LC-MS: (ES,m/z): 478. ¹H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), δ 8.17 (dd, J =8.2, 1.1 Hz, 1H), 7.59-7.31 (m, 2H), 7.12 (t, J = 8.0 Hz, 1H), 6.89-6.77(m, 2H), 6.76-6.62 (m, 2H), 4.54 (s, 2H), 3.81 (s, 3H), 3.29 (s, 2H),1.42 (s, 6H), 0.87 (s, 9H). 259 H-65

2-([5-(1-Ethyl-1H-indazol-6-yl)-1- ([pyridin-2-yl]methyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid SunFire: 36% ACN up to 50% in 7 minLC-MS: (ES, m/z): 420.2. ¹H NMR (300 MHz, DMSO) δ 8.50 (dd, J = 4.9, 1.7Hz, 1H), 8.07 (d, J = 0.9 Hz, 1H), 7.87 (t, J = 1.2 Hz, 1H), 7.78 (d, J= 8.4 Hz, 1H), 7.73 (dd, J = 7.7, 1.8 Hz, 1H), 7.27 (m, 2H), 7.07 (d, J= 7.8 Hz, 1H), 6.49 (s, 1H), 5.42 (s, 2H), 4.39 (m, 4H), 1.38 (s, 6H),1.33 (t, J = 7.2 Hz, 3H). 260 H-141

2-([1-[2-(Azetidin-1-yl)phenyl]-5-(3- cyclobutoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 55% ACN up to 70% in 7 minLC-MS: (ES, m/z): 462.1. ¹H NMR (300 MHz, DMSO-d6) δ 7.27 (td, J = 7.8,1.6 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.97 (td, J = 6.2, 3.2 Hz, 2H),6.75-6.64 (m, 3H), 6.61 (s, 1H), 6.50 (dd, J = 8.3, 1.3 Hz, 1H), 4.43(s, 2H), 4.29 (p, J = 7.1 Hz, 1H), 3.44 (dt, J = 14.4, 7.3 Hz, 4H),2.31-2.13 (m, 2H), 2.03 (p, J = 7.3 Hz, 2H), 1.95-1.82 (m, 2H),1.78-1.64 (m, 1H), 1.62-1.46 (m, 1H), 1.39 (s, 6H). 261 H-81

2-([1-[(2-chlorophenyl)methyl]-5-(1-ethyl-1H-1,2,3-benzotriazol-6-yl)-1H- pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 40% ACN up to 62% in 7 min LC-MS: (ES,m/z): 454. ¹H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.08 (d, J = 8.6Hz, 1H), 8.00 (t, J = 1.1 Hz, 1H), 7.50-7.37 (m, 2H), 7.31-7.23 (m, 2H),6.86-6.79 (m, 1H), 6.58 (s, 1H), 5.48 (s, 2H), 4.73 (q, J = 7.2 Hz, 2H),4.45 (s, 2H), 1.47 (t, J = 7.3 Hz, 3H), 1.41 (s, 6H). 262 H-128

(2R)-2-([1-(2-Chlorophenyl)-5-(3- cyclopropoxyphenyl)-1H-pyrazol-3-yl]methoxy)-2-methylbutanoic acid XSelect: 57% ACN up to 61% in 7 minLC-MS: (ES, m/z): 440.9. ¹H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H),7.69-7.38 (m, 4H), 7.22 (t, J = 8.0 Hz, 1H), 6.89 (ddt, J = 11.0, 7.6,1.1 Hz, 2H), 6.80 (dd, J = 2.4, 1.6 Hz, 1H), 6.66 (s, 1H), 4.45 (d, J =2.2 Hz, 2H), 3.55 (tt, J = 6.1, 2.9 Hz, 1H), 1.75 (hept, J = 7.0 Hz,2H), 1.38 (s, 3H), 0.86 (t, J = 7.4 Hz, 3H), 0.71-0.57 (m, 2H), 0.52-0.41 (m, 2H). 263 H-127

(2R)-2-Methyl-2-([1-(1-methyl-1H- indazol-7-yl)-5-[3-(2-methylpropoxy)-phenyl]-1H-pyrazol-3-yl]methoxy]- butanoic acid XSelect: 55% ACN up to71% in 7 min LC-MS: (ES, m/z): 477.1. ¹H NMR (300 MHz, DMSO-d6) δ 8.17(s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.24-7.10(m, 2H), 6.82- 6.75 (m, 3H), 6.61 (t, J = 2.0 Hz, 1H), 4.51 (s, 2H),3.41 (s, 3H), 3.32 (d, J = 6.7 Hz, 2H), 1.87-1.65 (m, 3H), 1.38 (s, 3H),0.89-0.81 (m, 9H). 264 H-132

(2R)-2-([5-(3,5-Dimethoxyphenyl)-1-[(2-ethoxyphenyl)methyl]-1H-pyrazol-3- yl]methoxy)-2-methylbutanoic acidXSelect: 60% ACN up to 64% in 7 min LC-MS: (ES, m/z): 469.0. ¹H NMR (300MHz, DMSO-d6) δ 7.21 (ddd, J = 8.7, 7.5, 1.7 Hz, 1H), 6.95 (dd, J = 8.4,1.0 Hz, 1H), 6.84 (td, J = 7.5, 1.0 Hz, 1H), 6.74 (s, 1H), 6.66 (dd, J =7.5, 1.7 Hz, 1H), 6.54-6.38 (m, 4H), 5.24 (s, 2H), 4.38 (d, J = 2.4 Hz,2H), 3.97 (q, J = 6.9 Hz, 2H), 3.65 (s, 7H), 1.85-1.59 (m, J = 7.4 Hz,2H), 1.34 (s, 3H), 1.21 (t, J = 6.9 Hz, 4H), 0.83 (t, J = 7.4 Hz, 3H)265 H-110

2-([1-[(2-Chlorophenyl)methyl]-5-[1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl]- 1H-pyrazol-3-yl]methoxy)-2-methylpropanoic acid XSelect: 48% ACN up to 52% in 7 min LC-MS: (ES,m/z): 459. ¹H NMR (300 MHz, DMSO-d6) δ 7.52- 7.44 (m, 1H), 7.35-7.20 (m,2H), 7.11 (s, 1H), 6.70 (dd, J = 6.9, 2.5 Hz, 1H), 6.48 (s, 1H), 5.50(s, 2H), 4.38 (s, 2H), 3.81 (s, 3H), 2.29 (s, 3H), 1.37 (s, 6H). 266H-153

(2R)-2-([1-[2-Azetidin-1-yl)phenyl]-5-(3-cyclopropoxyphenyl)-1H-pyrazol-3- yl]methoxy)-2-methylbutanoic acidSunFire: 72% ACN up to 82% in 7 min LC-MS: (ES, m/z): 462.3. ¹H NMR (300MHz, DMSO-d6) δ 7.29- 7.21 (m, 2H), 7.10-6.95 (m, 3H), 6.94- 6.84 (m,1H), 6.75-6.63 (m, 1H), 6.61 (s, 1H), 6.48 (d, J = 8.2 Hz, 1H), 4.43 (s,2H), 3.56-3.50 (m, 5H), 2.02 (q, J = 7.3 Hz, 2H), 1.74 (p, J = 7.1 Hz,2H), 1.37 (s, 3H), 0.85 (t, J = 7.4 Hz, 3H), 0.64 (d, J = 6.0 Hz, 2H),0.51 (q, J = 4.4, 3.3 Hz, 2H). 267 H-152

(2R)-2-([1-[2-(azetidin-1-yl)phenyl]-5-(1-propyl-1H-indazol-6-yl)-1H-pyrazol- 3-yl]methoxy)-2-methylbutanoicacid XSelect: 57% ACN up to 61% in 7 min LC-MS: (ES, m/z): 488.3. ¹H NMR(300 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.46 (s,1H), 7.26 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.09-7.00 (m,1H), 6.70 (d, J = 11.2 Hz, 2H), 6.48 (d, J = 8.2 Hz, 1H), 4.46 (s, 2H),4.15 (t, J = 7.1 Hz, 2H), 3.53-3.44 (m, 4H), 2.04 (q, J = 7.4, 6.7 Hz,2H), 1.74 (dq, J = 14.6, 7.3 Hz, 2H), 1.61 (h, J = 7.3 Hz, 2H), 1.38 (s,3H), 0.86 (t, J = 7.4 Hz, 3H), 0.72 (t, J = 7.4 Hz, 3H). 268 H-154

(2R)-2-([5-(1-ethyl-1H-indazol-6-yl)-1-[2-(pyrrolidin-1-yl)phenyl]-1H-pyrazol- 3-yl]methoxy)-2-methylbutanoicacid XSelect: 50% ACN up to 72% in 7 min LC-MS: (ES, m/z): 488. ¹H NMR(300 MHz, DMSO-d6) δ 12.71 (s, 1H), δ 7.96 (d, J = 0.9 Hz, 1H), 7.62 (d,J = 8.4 Hz, 1H), 7.46-7.40 (m, 1H), 7.24 (ddd, J = 8.5, 7.1, 1.6 Hz,1H), 7.07 (td, J = 6.7, 6.3, 3.3 Hz, 2H), 6.87-6.59 (m, 3H), 4.48 (s,2H), 4.23 (q, J = 7.2 Hz, 2H), 2.76 (d, J = 7.5 Hz, 4H), 1.74 (dh, J =14.0, 7.2 Hz, 4H), 1.62-1.50 (m, 2H), 1.38 (s, 3H), 1.20 (t, J = 7.2 Hz,3H), 0.86 (t, J = 7.4 Hz, 3H). 269 H-155

(2R)-2-([1-[2-(Azetidin-1-yl)phenyl]-5-(1-ethyl-1H-indazol-6-yl)-1H-pyrazol-3- yl]methoxy)-2-methylbutanoicacid XBridge: 44% ACN up to 54% in 7 min LC-MS: (ES, m/z): 474. ¹H NMR(300 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.50 (s,1H), 7.24 (t, J = 7.6 Hz, 1H), 7.08 (dd, J = 20.7, 8.1 Hz, 2H),6.88-6.58 (m, 2H), 6.46 (d, J = 8.4 Hz, 1H), 4.48 (s, 2H), 4.25 (q, J =7.2 Hz, 2H), 3.45 (dd, J = 22.1, 7.2 Hz, 4H), 2.18-1.88 (m, 2H), 1.71(dd, J = 15.0, 7.4 Hz, 2H), 1.33 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H), 0.84(t, J = 7.3 Hz, 3H).

The activity of the compounds in Examples 1-269 as MCT4 inhibitors isillustrated in the following assays. The other compounds listed above,which have not yet been made and/or tested, are predicted to haveactivity in these assays as well.

Biological Activity Assays

The following are assays that may be used to evaluate the biologicalefficacy of compounds of Formula (I) in a manner similar to thatpreviously reported for MCT1 and MCT4 and are known to those with skillin the art. See, e.g., Murray, C. M. et al., “Monocarboxylatetransporter MCT1 is a target for immunosuppression,” Nature chemicalbiology 1, 371-376 (2005); and Ovens, M. J., et al., “AR-C155858 is apotent inhibitor of monocarboxylate transporters MCT1 and MCT2 thatbinds to an intracellular site involving transmembrane helices 7-10,”The Biochemical Journal 425, 523-530, (2010).

Preparing BCECF-Loaded Cells

Cells (˜7×10⁶) are trypsinized (0.05% Trypsin-EDTA), pelleted (300 g, 5min), and resuspended in 1 mL Tyrode's Solution, pH 7.4 (119 mM NaCl, 5mM KCl, 25 mM HEPES, pH 7.4, 2 mM CaCl₂, 2 mM MgCl₂, 6 g/L glucose). 10□L of a 30 mM DMSO stock of BCECF-AM ester (Life Technologies) is addedand the cells are incubated at 37° C. for 5 min. The cells are pelleted(300 g, 5 min), washed once with 1 mL Tyrode's Solution, pH 7.4,re-pelleted (300 g, 5 min), and resuspended in 1 mL Tyrode's Solution,pH 7.4.

Assay 1: Lactate Transport in MCT4-Expressing MDA-MB-453 Breast CancerCells.

MCT4 may be stably expressed in MDA-MB-453 breast cancer cells that donot express native MCT1 or MCT4. MCT4 activity may be assessed bymonitoring the intracellular pH change that accompanies lactate/protonsymport, using the pH-sensitive fluorescent dye2′,7′-bis-(carboxyethyl)-5(6)-carboxyfluorescein (BCECF), in a mannersimilar to that previously reported for MCT1 and MCT4. The following isan exemplary procedure for assaying MCT4 activity of the compounds ofFormula (I).

Assay 2: MCT4-Mediated Lactate Transport in NCI-H358 Lung AdenocarcinomaCells.

NCI-H358 lung adenocarcinoma cells may be used to measure MCT4 activityin cells with high native levels of MCT4 and low levels of MCT1 and areknown to those with skill in the art. Preparation of BCECF-loaded cellsand lactate transport activity may be determined as described for Assay1.

Assay 3: MCT4-Mediated Lactate Transport in MDA-MB-231 Breast CancerCells.

MDA-MB-231 breast cancer cells may be used to measure MCT4 activity incells with high native levels of MCT4 and low levels of MCT1 and areknown to those with skill in the art. MCT4 activity may be assessed bymonitoring the intracellular pH change that accompanies lactate/protonsymport, using the pH-sensitive fluorescent dye2′,7′-bis-(carboxyethyl)-5(6)-carboxyfluorescein (BCECF), in a mannersimilar to that previously reported for MCT1 and MCT4. The following isan exemplary procedure for assaying MCT4 activity of the compounds ofFormula (I).

Assay 4: MCT1-Mediated Lactate Transport in BT20 Breast Cancer Cells.

MCT1 activity may be measured using BT-20 breast cancer cells thatexpress high native levels of MCT1, but do not express MCT4 and areknown to those with skill in the art. Preparation of BCECF loaded cellsare as described for Assay 1. Lactate transport assay is as describedfor Assay 1, except 10 mM L-lactate (rather than 50 mM) is added.

Results of the assays above are given below in Tables 26 and 27, inwhich “ND” means no data. As can be seen, most compounds disclosedherein are selective for MCT4 over MCT1.

TABLE 26 MCT Activity. MCT1 IC₅₀ MCT4 IC₅₀ (nM) MCT4 IC₅₀ (nM) (nM)Example MDA-MB-453 + MCT4 NCI-H358 BT20 1 340 140 50,000 2 450 24029,000 3 72 60 25,000 4 68 54 33,000 5 160 63 1,800 6 2,400 4,600 6,6007 720 460 70,000 8 69 81 46,000 9 320 340 39,000 10 21 33 8,800 11 45 2529,000 12 38 49 58,000 13 20 22 17,000 14 26 44 >100,000 15 900440 >33,000 16 1,000 640 73,000 17 440 860 1,200 18 5,300 4,200 45,00019 110 160 57,000 20 17,000 22,000 7,900 21 35,000 48,000 300,000 2214,000 39,000 150,000 23 1,500 2,100 >300,000

TABLE 27 MCT Activity. MCT4 IC₅₀ (nM) MCT1 IC₅₀ MDA-MB- (nM) Ex. 231BT20 14 30 >100,000 24 30 >100,000 25 33 77,000 26 9.4 27,000 27 1 5,60028 12 15,000 29 3.7 16,000 30 8.8 27,000 31 53 42,000 32 79 83,000 333.2 9,100 34 9.3 >11,000 35 5.2 59,000 36 82 50,000 37 7.6 8,400 38 4860,000 39 5.4 10,000 40 520 >100,000 41 55 1,200 42 2.6 9,800 4313 >33,000 44 1.1 8,400 45 19 12,000 46 142 47,000 47 410 >100,000 48 8955,000 49 240 130,000 50 70 34,000 51 15 6,000 52 190 84,000 53160 >100,000 54 37 27,000 55 260 >100,000 56 8,000 >133,000 57110 >133,000 58 150 78,000 59 340 81,000 60 13 44,000 61 3.1 11,000 6233 27,000 63 37 17,000 64 8.3 45,000 65 8 13,000 66 7.8 45,000 67 1117,000 68 9.1 26,000 69 5,800 >100,000 70 9,300 >100,000 71 34,00064,000 72 220 45,000 73 21 >11,000 74 6,400 >100,000 75 1,700 >100,00076 400 38,000 77 340 9,000 79 59 15,000 80 81 61,000 81 6,300 6,600 82460 16,000 101 3.4 12,000 102 15 42,000 103 2.6 28,000 104 20 12,000 1057.6 15,000 106 12 21,000 107 170 9,900 108 36 5,200 109 2.1 >11,000 11020 30,000 111 7.9 32,000 112 29 94,000 113 6.7 33,000 114 4.3 73,000 11534,000 >100,000 116 11,000 61,000 117 430 >100,000 118 170 50,000 119 6765,000 120 4 22,000 121 8 21,000 122 50 2,500 123 1,500 11,000 124 42031,000 125 5,900 61,000 126 130 35,000 127 41 15,000 128 1.2 >11,000 1292.8 16,000 130 98 55 131 225 650 132 8.6 8,200 133 13 >33,000 134 3872,000 135 53 220 136 920 >33,000 137 1,400 >100,000 138 535 >100,000139 9,700 >100,000 140 8.3 16,000 141 6.7 33,000 142 6.3 26,000 143 1953,300 144 127 2,400 150 2.8 25,000 151 3.6 70,000 152 80 >100,000 153830 44,000 154 240 >100,000 155 0.32 >33,000 156 1400 >100,000 157 2686,000 158 580 >100,000 159 11 >100,000 160 270 >100,000 161 3.3 22,000162 6.4 34,000 163 4.4 73,000 164 43 >100,000 165 85 99,000 166 5.953,000 167 0.59 36,000 168 1.7 61,000 169 12.2 68,000 170 2.0 32,000 17112 32,000 172 0.59 33,000 173 230 66,000 174 101 >100,000 175 5.1 28,000176 180 >100,000 177 1.4 35,000 178 2.5 27,000 179 13 >100,000 180 2.928,000 181 20 25,000 182 5.9 12,000 183 1.3 86,000 184 22 >33,000 1859.3 17,000 186 21.5 90,000 187 43 63,000 188 7.5 15,000 189 18 22,000190 7.8 31,000 191 17 16,000 192 190 47,000 193 18 38,000 1943500 >100,000 195 5.3 13,000 196 1.9 38,000 197 2000 76,000 198 3.526,000 199 9.6 34,000 200 1.9 17,000 201 7.2 15,000 202 6.2 23,000 203185 93,000 204 40 >100,000 205 890 >100,000 206 16 45,000 207 15 3,200208 7.5 17,000 209 31 95,000 210 2.4 7,300 211 2.4 20,000 212195 >100,000 213 12 12,000 214 6.0 94,000 215 360 >100,000 216 N.D. N.D217 8.7 18,000 218 7.5 22,000 219 4.0 14,000 220 0.54 33,000 221 3.238,000 222 3.9 94,000 223 0.3 21,000 224 4.1 30,000 225 N.D. N.D. 226 1554,000 227 690 37,000 228 5.9 31,000 229 1.9 42,000 230 8.1 92,000 2314.5 63,000 232 2.1 29,000 233 700 >100,000 234 960 70,000235 >30,000 >100,000 236 170 >100,000 237 160 >100,000 238 3.7 21,000239 150 >100,000 240 28 62,000 241 25 8,500 242 59 57,000 243 23 78,000244 68 16,000 245 7.6 77,000 246 3.10 32,000 247 23.00 >100,000 248560.00 >100,000 249 39.00 >100,000 250 1.30 41,000 251 5.60 98,000 25225.00 43,000 253 19.00 55,000 254 285.00 >100,000 255 2.40 7,300 2562.60 17,000 257 0.35 19,000 258 12.00 27,000 259 850.00 >100,000 2600.83 26,000 261 17.00 43,000 262 9.10 7,900 263 2.20 16,000 264 0.3510,000 265 5.60 84,000 266 0.36 64,000 267 0.57 11,000 268 0.30 36,000269 1.00 58,000 N.D. = not determined

Metabolic Stability Assays

The following are assays that may be used to evaluate the metabolicstability of compounds of Formula (I) in human, rat, or mousemicrosomes. The assays follow a common procedure recited below.

1. Master solution: 200 □L of 200 mM Phosphate buffer, 106 □L ofultra-pure water, 40 □L of 50 mM MgCl₂, and 10 □L of 20 mg/mL livermicrosomes (human, rat, or mouse).

2. Two separated experiments were performed as follows. a) With NADPH:10 μL of 20 mg/mL liver microsomes and 40 μL of 10 mM NADPH were addedto the incubations. The final concentrations of microsomes and NADPHwere 0.5 mg/mL and 1 mM, respectively. b) Without NADPH: 10 μL of 20mg/mL liver microsomes and 40 pt of ultra-pure H₂O were added to theincubations. The final concentration of microsomes was 0.5 mg/mL.

3. The reaction was started with the addition of 4 μL of 200 μM controlcompound or test compound solutions. Verapamil was used as positivecontrol in this study. The final concentration of test compound orcontrol compound was 2 μM.

4. Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30,45 and 60 min. The reaction was stopped by the addition of 4 volumes ofcold acetonitrile with IS (100 nM alprazolam, 200 nM labetalol and 2 μMketoprofen). Samples were centrifuged at 3,220 g for 40 minutes. A 90 μLaliquot of the supernatant was mixed with 90 μL of ultra-pure H₂O andthen used for LC-MS/MS analysis.

5. Data analysis. All calculations were carried out using MicrosoftExcel. Peak areas were determined from extracted ion chromatograms. Theslope value, k, was determined by linear regression of the naturallogarithm of the remaining percentage of the parent drug vs. incubationtime curve. The in vitro half-life (in vitro t_(1/2)) was determinedfrom the slope value: in vitro t_(1/2)=−(0.693)/k.

Results are given below in Table 28, wherein “ND” means no data.

TABLE 28 Metabolic Stability. Human Human Mouse Mouse Rat Rat micro-micro- micro- micro- micro- micro- some some % some some % some some %Ex. t_(1/2), min 60 min t_(1/2), min 60 min t_(1/2), min 60 min 14 24582 1300 95 ND ND 27 50 43 61 50 ND ND 35 115 67 35 31 ND ND 36 290 851200 99 ND ND 38 76 56 79 61 ND ND 39 380 89 370 88 ND ND 54 78 59 76095 ND ND 57 190 80 >2000 100 ND ND 64 200 82 270 84 ND ND 65 140 78 56092 ND ND 66 120 73 260 83 ND ND 68 790 95 380 91 ND ND 110 2377 99 22386 549 94 120 198 81 410 101 51 44 121 198 82 186 81 86 61 132 116 70 9864 112 70 133 1006 97 344 90 404 91 134 186 80 109 72 264 85 140 109 6764 62 59 48 150 341 90 ∞ 103 1715 98 155 52 62 38 37 73 70 157 149 789639 102 748 97 161 194 82 ∞ 99 259 80 166 1265 94 194 82 ∞ 102 167 25084 430 97 74 72 168 187 78 229 81 173 81 170 471 87 ∞ 99 ∞ 95 175 212 83711 94 315 87 177 184 75 334 87 634 90 178 115 66 125 70 145 72 179 64493 ∞ 98 318 85 180 276 88 ∞ 103 2293 98 183 99 66 122 73 101 71 188 ∞101 1400 92 490 87 191 1405 98 1005 97 556 94 196 88 62 37 33 38 32 198207 80 243 84 205 82 201 83 58 83 58 45 39 202 37 32 38 32 11 2 211 18078 49 43 73 57 220 ∞ 105 1038 102 292 86 221 68 56 38 34 37 33 222 ∞ 1101004 94 335 90 224 736 91 829 98 132 73 226 468 95 682 95 455 88 228 13071 767 96 395 91 229 103 64 196 81 109 69 232 97 65 73 59 70 50 243 43388 1301 97 302 88 246 95 65 168 81 109 69 251 181 77 93 63 181 83 2571297 96 ∞ 102 ∞ 103

Pharmacokinetic Assays in Mouse and Rat

The following are assays that may be used to evaluate thepharmacokinetic properties of Formula (I) in mouse or rat. The assaysfollow a common procedure recited below.

1. Formulations: For IV, DMSO/PEG400/30% HP-□-CD (10:20:70). For PO(oral gavage), DMSO/PEG400 (10:90). Formulations freshly prepared on theday of dosing or prior to dosing. Storage at room temperature.

2. Test Species: For Mouse: Male CD1 strain, approximately 6-8 weeks inage, approximately 20-30 g. For Rat: Male Sprague-Dawley strain,approximately 6-8 weeks in age, approximately 200-300 g.

3. Dose Level: For IV, 3 mg/kg. For PO, 10 mg/kg.

4. Number of animals: 3 per assay.

5. PK time points: For IV (plasma): 5 min, 15 min, 1, 2, 4, 6, 8, 24 hpost dose. For PO (plasma): 15 min, 30 min, 1, 2, 4, 6, 8, 24 h postdose.

6. Blood Sample Collection and Processing. Blood was collected (˜0.2 mLper time point) from jugular vein. Blood of each sample was transferredinto plastic micro centrifuge tubes containing anticoagulant of EDTA-K₂.Blood samples were centrifuged at 2,000 g for 5 minutes at 4° C. toobtain plasma.

7. Samples Analysis: Plasma samples were analyzed using LC/MS/MS method,and pharmacokinetic parameters (half-life: t_(1/2); oralbioavailability: F; volume of distribution: Vss).

Results are given below in Table 29, where “ND” means no data.

TABLE 29 Pharmacoknetic Properties in Rodents. Mouse t_(1/2) Mouse FMouse Vss Rat t_(1/2) Rat F Rat Vss Ex. (h) (%) (L/kg) (h) (%) (L/kg) 145.4 100  0.79 3.8 64 1.3 110 26.7  100  0.81 4.7 84 0.34 150 4.9 89 9.93.6 43 1.2 161 ND ND ND 5.7 61 0.32 167 1.7 24 2.6 2.2 72 1.2 170 2.6100 2.0 2.4 18 1.1 175 ND ND ND 4.2 48 0.40 179 ND ND ND 2.2 76 0.30 180ND ND ND 4.4 49 0.39 191 ND ND ND 6.3 97 1.0 211 1.9 57 1.5 3.6 55 3.6220 6.9 100 1.7 2.8 29 0.68 224 ND ND ND 2.6 53 1.3 228 4.4 100 2.0 3.194 1.3 229 4.2 100 1.9 2.7 100 1.0 232 3.1 56  0.21 2.6 52 0.15 246 NDND ND 4.7 52 1.7 251 ND ND ND 3.0 98 0.38 257 3.6 76 2.8 2.7 76 1.6 2605.2 86  0.22 3.7 85 0.20 264 2.7 94 1.1 4.6 100 2.5 266 3.8 100  0.362.7 100 0.23 267 3.3 64 3.9 2.6 54 7.7 268 2.7 77  0.77 2.2 57 0.76 2693.3 100 1.3 ND ND ND

Adjuvant-Induced Arthritis Model in Rat

The following assays are used to evaluate anti-inflammatory propertiesof Formula (I) in rat. The assays follow a common procedure recitedbelow.

1. Formulation: 0.5% Methylcellulose in saline. Formulation freshlyprepared on day of dosing.

2. Test Species: SD rat, approximately 6-8 weeks in age, approximately200 g.

3: Arthritis Induction Procedure: Complete Freund's Adjuvant (CFA; 50□L/rat, M. Tuberculosis at 4 mg/mL) was administered via left pawsub-plantar injection.

4: Dosing: PO (oral gavage), 3 days post CFA injection.

5: Body Weight. Body weights of all animals were recorded during thecourse of study, at Day 1 and Day 3.

6: Difference of Weight Bearing Test (DWB). Distribution of body weightof rats between CFA-injected and contra-lateral paws were measured byweight balance changing instrument. Animals were tested to register theweight load exerted by the hind paws by means of a force plate insertedin the floor. The mean weight bearing (in g) between CFA injected pawand contra-lateral paw were determined over 10 seconds. Measurementswere taken three times, including baseline prior to dose, 1 hour, and 4hours post dosing on Day 3.

7: Mechanical Allodynia Test (MA). Mechanical allodynia of the left hindpaw will be measured during course of study by determining withdrawalthresholds to Von Frey filament. The filament was appliedperpendicularly to the plantar surface of the paw with increasing force.The threshold for paw withdrawal was calculated by taking the average of2-3 repeated stimuli (in g) which induced a reflex paw withdrawal.Measurements were taken three times, including baseline prior to dose, 1hour, and 4 hours post dosing on Day 3.

8: Minimal Efficacious Dose was determined by comparison of Formula (I)compounds to positive control Dexamethasone.

TABLE 31 Efficacy in Rat Adjuvant-Induced Arthritis Model Difference inWeight Mechanical Allodynia (Von Bearing, Minimal Frey), MinimalEfficacious Ex. Efficacious Dose (mg/kg) Dose (mg/kg) 14 30 30 110 10 10150 10 10 161 ≤10 ≤10 170 3 3 175 >10 >10 179 ≤10 ≤10 180 >10 >10191 >10 >10 220 3 3 224 ≤10 ≤10 229 3 3 232 1 1 260 1 1 264 1 1 266 3 3267 3 3 268 1 1

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein intheir entireties. Where any inconsistencies arise, material literallydisclosed herein controls.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of structural Formula II:

or a salt thereof, wherein: L is chosen from a bond, methylene, andethylene; W is chosen from

Y is chosen from

R^(2c) is chosen from H, C₁-C₄alkoxy and C₁-C₄cycloalkoxy; R^(2d) ischosen from null and C₁-C₄alkoxy; R^(2e) is C₁-C₄alkyl; Z is chosen from

n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl); R⁴ and R⁵ areindependently chosen from H and C₁-C₆alkyl, wherein R⁴ and R⁵ togethercomprise no more than 6 carbons and wherein at least one of R⁴ and R⁵ isC₁-C₆alkyl, or R⁴ and R⁵, together with the atoms to which they areattached, form a 3-7 membered cycloalkyl or heterocycloalkyl ring; R⁶ ischosen from H and C₁-C₄alkyl; and R⁹ is chosen from halo, amino, andC₁-C₄alkoxy.
 2. The compound as recited in claim 1, having structuralFormula III:

or a salt thereof, wherein: L is chosen from a bond, methylene, andethylene; R^(2c) is chosen from H, C₁-C₄alkoxy and C₁-C₄cycloalkoxy;R^(2d) is chosen from null and C₁-C₄alkoxy; R^(2e) is C₁-C₄alkyl; Z ischosen from

R⁴ and R⁵ are independently chosen from H and C₁-C₆alkyl, wherein R⁴ andR⁵ together comprise no more than 6 carbons and wherein at least one ofR⁴ and R⁵ is C₁-C₆alkyl, or R⁴ and R⁵, together with the atoms to whichthey are attached, form a 3-7 membered cycloalkyl or heterocycloalkylring; R⁶ is chosen from H and C₁-C₄alkyl; and R⁶ is chosen from H andmethyl.
 3. The compound as recited in claim 1, wherein W is chosen fromand

R⁴ and R⁵ are independently chosen from H, methyl, and ethyl, andwherein at most one of R⁴ and R⁵ is H.
 4. The compound as recited inclaim 3, wherein Z is


5. The compound as recited in claim 2, wherein R^(2d) is chosen from Hand alkoxy.
 6. The compound as recited in claim 5, wherein R^(2c) isalkoxy.
 7. The compound as recited in claim 6, wherein R⁴ and R⁵ areindependently chosen from H, methyl, and ethyl, and wherein at most oneof R⁴ and R⁵ is H.
 8. The compound as recited in claim 7, wherein Z is


9. The compound as recited in claim 1, wherein the compound hasstructural Formula VII:

or a salt thereof, wherein: L is chosen from a bond and methylene; W ischosen from

Y is chosen from

R^(2c) is chosen from H, C₁-C₄alkoxy and C₁-C₄cycloalkoxy; R^(2d) ischosen from null and C₁-C₄alkoxy; R^(2e) is C₁-C₄alkyl; Z is chosen from

n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl); R⁴ and R⁵ areindependently chosen from C₁-C₃alkyl; R⁶ is chosen from H andC₁-C₄alkyl; and R⁹ is chosen from halo, amino, and C₁-C₄alkoxy.
 10. Thecompound as recited in claim 9, wherein W is


11. The compound as recited in claim 10, wherein n is 1, formingazetidin-1-yl.
 12. The compound as recited in claim 11, wherein L is abond.
 13. The compound as recited in claim 1, wherein compound hasstructural Formula VIII:

or a salt thereof, wherein: L is chosen from a bond and methylene; Y ischosen from

R^(2c) is chosen from H, C₁-C₄alkoxy and C₁-C₄cycloalkoxy; R^(2d) ischosen from null and C₁-C₄alkoxy; R^(2e) is C₁-C₄alkyl; R⁴ and R⁵ areindependently chosen from C₁-C₃alkyl; and R⁶ is chosen from H andC₁-C₄alkyl.
 14. The compound as recited in claim 13, wherein Y is


15. The compound as recited in claim 13, wherein n is 1, formingazetidin-1-yl.
 16. The compound as recited in claim 15, wherein L is abond.
 17. The compound as recited in claim 16, wherein Y is


18. The compound as recited in claim 1, wherein the compound hasstructural Formula XI:

or a salt thereof, wherein: W is chosen from

m is 1, 2, or 3 (forming a cyclopropyl, cyclobutyl, or cyclopentyl); Lis chosen from a bond and methylene; Z is chosen from

n is 1 or 2 (forming an azetidin-1-yl or pyrrolidin-1-yl); R⁴ and R⁵ areindependently chosen from C₁-C₃alkyl; R⁶ is chosen from H andC₁-C₄alkyl; and R⁹ is chosen from halo, amino, and C₁-C₄alkoxy.
 19. Thecompound as recited in claim 18, wherein W is


20. The compound as recited in claim 19, wherein L is a bond.
 21. Thecompound as recited in claim 18, wherein R⁹ is chosen from chloro,dimethylamino, and ethoxy.
 22. The compound as recited in claim 21,wherein R⁹ is chosen from chloro and ethoxy.
 23. The compound as recitedin claim 18, wherein n is 1, forming azetidin-1-yl.
 24. The compound asrecited in claim 1, wherein W is


25. The compound as recited in claim 24, wherein R⁹ is chosen fromchloro and ethoxy.
 26. The compound as recited in claim 25, wherein L isa bond.
 27. The compound as recited in claim 26, wherein: Y is

R^(2d) is chosen from null and C₁-C₄alkoxy; and R^(2e) is C₁-C₄alkyl.28. The compound as recited in claim 27, wherein: R^(2c) is chosen frommethoxy, methylpropoxy, cyclopropoxy, and cyclobutoxy; and R^(2d) ischosen from null and methoxy.
 29. A compound chosen from:

or a salt thereof.
 30. An isolated enantiomer of a compound as recitedin claim
 29. 31. A pharmaceutical composition comprising a compound asrecited in claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier, adjuvant, or vehicle.
 32. A methodfor inhibiting activity of the monocarboxylate transporter MCT4, or amutant thereof, in a biological sample comprising the step of contactingsaid biological sample with a compound as recited in claim 1, or a saltthereof.